5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2 (3H)-ones useful as HIV reverse transcriptase inhibitors

ABSTRACT

The present invention relates to benzoxazepinones of formula I: ##STR1## or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same and methods of using the same for treating viral infection or as an assay standard or reagent.

This application claims the benefit of U.S. Provisional Application No. 60/057,431, filed Sep. 2, 1997.

FIELD OF THE INVENTION

This invention relates generally to 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2(3H)-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits Comprising the same, and methods of using the same for treating viral infection or as assay standards or reagents.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptoitatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, aid causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxythymidinene (d4T), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxy-3'-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describes reverse transcriptase inhibitors which are benzoxazinones of the formula: ##STR2## wherein X is a halogen, Z may be O. However, benzoxazinones are not part of the present invention.

U.S. Pat. No. 4,476,133 depicts CNS active 4,1-benzoxazepines of the formula: ##STR3## wherein A--B can be NH--C(O), R is H or C₁₋₅ alkyl, X is H, halo, or NO₂, and Y is phenyl or pyridyl. No mention is made of 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepin-2(3H)-ones which are the subject of the present invention.

EP 0,142,361 illustrates phoepholipase A₂ inhibitors of the formula: ##STR4## wherein R₁ can be a variety of cyclic and acyclic groups, but not hydrogen, R₂ is H, alkyl, or phenyl, and Y₁ is H, halo, NO₂ or CF₃. Compounds of the present invention have a hydrogen at the 1-position and do not have a phenyl group directly attached to the 5-position.

EP 0,567,026 and JP 08/259,417, which have similar disclosures, describe 4,1-benzoxazepinone derivatives of the formula: ##STR5## wherein ring A may be optionally substituted phenyl (also optionally substituted heteroaryl in JP '447), R₁, R₂, and R₃ can be a variety of groups including H and optionally substituted hydrocarbon, X is a bond or spacer and Y (B in JP '447) is optionally substituted cerboxyl, hydroxyl, amino, phenyl, carbamoyl, or a nitrogen-containing heterocycle. In JP '447, B is only optionally substituted phenyl or nitrogen-containing heterocycle. Compounds of this sort are not within the presently claimed invertion.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR6## wherein A, W, X, Y, Z, R^(a), R^(b), R¹ and R² are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF IREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: ##STR7## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(a) is selected from H, CF₃, CF₂ H, cycPr, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰ ;

R^(b) is selected from H, CF₃, CF₂ H, cycPr, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰ ;

alternatively, R^(a) and R^(b) together form --(CH₂)n--;

R¹ is selected from CF₃, CF₂ H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R² is selected from --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

provided that when either of R^(a) or R^(b) is phenyl, then R¹ is other than C₁₋₄ alkyl and C₃₋₅ cycloalkyl and R² is other than --(CH₂)_(p) CHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7b), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ _(O--;)

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷, at each occurrence, is selected from H and C₁₋₃ alkyl;

R^(7a), at each occurrence, is selected from H and C₁₋₃ alkyl;

R^(7b), at each occurrence, is C₁₋₃ alkyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R₁₀ ;

R⁹, at each occurrence, is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰, at each occurrence, is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹, at each occurrence, is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

n, at each occurrence, is selected from 1, 2, 3, 4, and 5; and,

p, at each occurrence, is selected from 0, 1, and 2.

[2] In a preferred embodiment, the present invention provides a novel compound of formuLa I, wherein:

R^(a) is H;

R^(b) is selected from H, CF₃, CF₂ H, cyclopropyl, CH═CH₂, and C₁₋₄ alkyl;

R¹ is selected from CF₃, CF₂ H, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and,

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ _(O--)), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.

[3] In a more preferred embodimeit, the present invention provides a novel compound of formula I, wherein:

A is O;

R¹ is selected from CF₃, CF₂ H, C₂ H₅, isopropyl, and cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃ ;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7b), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ _(O--;)

R⁵ is selected from H and F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R₁₀ ;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and,

p is selected from 1 and 2.

[4] In an even more preferred emodiment, the present invention provides a novel compouid of formula I, wherein:

R^(b) is selected from H, CF₃, CF₂ H, cyclopropyl, CH═CH₂, CH₃, and CH₂ CH₃ ;

R¹ is selected from CF₃, CF₂ H, and cyclopropyl;

R² is selected from --C.tbd.C--R⁸ and trans-CH═CR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, and I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatdms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.

[5] In a further preferred embodiment, the compound of the present invention is selected from:

5-(1-Butynyl)-7-chloro-1,5-dihydro)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-5-(1-Butynyl)-7-chloro)-1,5-dihydro-3-phenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazepin-2-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-1benzoxazepin-2(3H)-one;

trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S) -trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S) -trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(3S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

(+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6, 7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Methylenedioxy-5-2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-6,7-Methylenedioxy-5-2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; and,

rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;

or a pharmaceutically acceptable salt form thereof.

[6] In another preferred embodiment, the present invention provides a compound of formula II: ##STR8## or a stereoisomer or pharmaceutically acceptable salt form thereof.

[7] In another more preferred emodiment, the present invention provides a compound of Formula IIa: ##STR9## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R¹ is CF₃.

In a second embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a third embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a fourth embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.

In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, efavirenz, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, efavirenz, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.

In another still further preferred embodiment, the protease inhibitor is indinavir.

In a fifth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a sixth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.

In a seventh embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is will known in the art how to prepare optically active forms, sich as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereoneric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or nore. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a steble compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By any of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶, occurs more than one time in any constituent or formula formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring, then a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of subtituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachlorocethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cyclcoalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon--carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon--carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, "aryl" or "aromatic residue" is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a staole 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms nay optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazLnyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-ocadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, piperazin.l, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, -thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Exanples of non-nucleoside RT inhibitors include, but are not limited to, efavirenz (DuPont), rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).

As used herein, "HIV protease inhibitor" is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saqlinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), DMP450 (DuPont), DMP850 (DuPont), DMP851 (DuPont) and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO94/19329, WO94/22840, and PCT Aplication Number US 96/03426 and the protease inhibitors disclosed in WO94/04993, WO95/33464, WO96/28,418, and WO96/28,464.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organdc acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxylenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized fron the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like other, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and andmals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of e compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compourd. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol end amine functional groups in the compounds of the present invention, and the like.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds arE. contemplated by the present invention.

"Therapeutically effective anount" is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is nost clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect cf the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods Inown in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference. ##STR10## Scheme 1 illustrates a method of making the oxazepinones of the present invention starting from an appropriately substituted aminoalcohol. The amine is acylated by an α-halo acid halide (preferably an α-bromoacyl bromide) in the presence of a weak base such as pyridine. After acylation, cyclization is effected by further treatment with base. A tertiary amine base such as diisopropylethylamine, sodium hydride, potassium hydride, lithium hydride, sodium carbonate, potassium carbonate or cesium carbonate, sodium or potassium alkoxides or similar bases may be used with cesium carbonate and sodium hydride being preferred. Any non-protic organic solvent may be used for tie cyclization reaction with DMF being preferred. In cases where R¹ and R² are different and R^(a) and R^(b) are also different, two diastereomers are formed which may be separated by selective crystallization or chromatography. In the case where R¹ and R² are different and either R^(a) or R^(b) is H, cyclization with cesium carbonate in the presence of lithium bromide or lithium iodide will often afford a diastereomeric mixture ii which one diastereomer greatly predominates. Thus, in some cases these cyclization conditions are greatly preferred. In cases where both R^(a) and R^(b) are H, either sodium hydride or cesium carbonate are preferred bases. When an appropriately strong base is used, both acylation and cyclization reactions illustrated in Scheme 1 may be effected in a single step. ##STR11## Scheme 2 illustrates a second method of making the oxazepinones of the present invention starting from an appropriately substituted N-tritylaminoalcohol. The hydroxy group is alkylated with an α-haloester in the presence of base, and then after removal of the trityl protecting group, treatment with base and/or heat effects cyclization to the oxazepinone. In some cases it may be preferable to use an unprotected amino group. Also, other protecting groups known to those of skill in the art can be used in place of the shown trityl group. ##STR12## Scheme 3 illustrates a meth)d of making 5,5-disubstituted-benzoxazepin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. In Scheme 3, G can be R³, R4, R⁵ or R⁶ or a combination of two or more of these groups. The acid is converted to its N-methoxy-N-methyl amide derivative which cal then be displaced to obtain the R¹ -substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized by the 2-step procedure described in Scheme 1. ##STR13## Scheme 4 describes a means of obtaining 5-trifluoromethyl-benzoxazepin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 5-substituent can then be added through andon attach on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1. ##STR14## Because certain benzo-substituents are incompatible with the methods of the previous schemes, it may be necessary to protect these groups before forming the benzoxazepinone. In Scheme 5 there is shown a means of obtaining carbonyl-substituted 5,5-disubstituted-benzoxazepin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol The same procedures as in Scheme 4 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl₂ and HgO or other means well known to those of skill in the art. ##STR15## A method for forming 5,5-disubstituted-benzoxazepin-2-ones, wherein R² is a vinyl or alkynyl group, is described in Scheme 6. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 3 or 4, an acetylide is added. The prodict can be deprotected and cyclized in two steps (Scheme 1) to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH₄, deprotection by standard means, and 2-step cyclization. ##STR16## The acetylide which is required for the reactions illustrated in Scheme 6 may be generated directly from a terminal acetylene by treatment wLth a strong base such as n-butyllithium. An alternate methol for generating an acetylide, illustrated in Scheme 6A, is by converting an aldehyde to a 1,1-dibromoolefin which is then reacted with 2 equivalents of n-butyllithium. ##STR17## Scheme 7 describes an alterrate route to 5,5-disubstituted-benzoxazepin-2-ones from andlines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R² group can then be added, e.g. via an acetylide, followed by cyclization as in Scheme 1. ##STR18## An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 4. Reduction and reoxidation removes the chloro group leaving the desired intermediate. ##STR19## Scheme 9 describes a novel n ethod of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 3, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of tne shown trityl group. ##STR20## Scheme 10 illustrates specific steps of Scheme 9. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃ CF₂, and CF₃ CF₂ CF₂) is useful for making same of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF₃ CF₂ TMS, CF₃ CF₂ CF₂ TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride andon such as sodium fluoride, potassium fluoride, lithium fluoride, cesilm fluoride as well as oxyandonic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents suich as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyandonic species. The reaction can be typically carried out at temperatures between about -20° C. to about 50° C., preferably about -10 to about 10° C., more preferably about 0° C.

Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO₂, PDC, PCC, K₂ Cr₂ O₇, CrO₃, KMnO₄, BaMnO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant is MnO₂. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane, dichloroethane, or tetrachloroethane, preferably dichloromethane. ##STR21## An additional means of making 5-alkynyl-benzoxazepin-2-ones is shown in Scheme 11. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound. ##STR22## In addition to the methods of obtaining keto-anilines described in Schemes 3 and 4, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 12. This reaction is accomplished by using an andonic nucleophile of the group R^(Ia). See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.

It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0) of anion (or anion precursor) is preferred to force he conversion and improve the isolated yield. Preferably, the temperature used is from -20 to +35° C., with temperatures below 0° C. being more preferred and -20° C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent. ##STR23## Scheme 13 illustrates the synthesis of a 3,3-disubstituted oxazepinone from a monosubstituted oxazepinone. After first protecting the ring nitrogen with one of several amide protecting groups known to those skilled in the art, treatment with a strong base followed by an alkyl iodide gives after protecting group removal, a 3,3-disubstituted oxazepinone. Using the same sequence of reactions, a 3-monosubstituted oxazepinone (R^(a) adove is H) can also be synthesized from a 3-unsubstituted oxazepinone. ##STR24## Compounds of the present intention that are thioamides can be prepared as illustrated in Scheme 14 by treating the corresponding amides with either Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] or phosphorous pentasulfide. ##STR25## Compounds of the present invention in which R^(a) or R^(b) are vinyl or cyclopropyl can be prepared as illustrated in Scheme 15. 2-Aminoarylketones protected, for example, with an N-p-methoxybenzyl (PMB) group can be treated with an acetylide to give the corresponding acetylenic alcohol. Cyclization can be effected by 2,4-dibromobutyryl chloride and the PMB group can then be removed, for example, by treatment with ceric ammonium nitrate. Displacement cf the bromide with an arylselenide followed by oxidative elimination by treatment with hydrogen peroxide affords the 5-alkynyl-3-vinylbenzoxazepinone. The vinyl group can be converted to a cyclopropane ring by Pd(II) catalylzed reaction with diazomethane. If the acetylenic alcohol is reduced to the olefin with lithium aluminum hydride (LAH), the same reaction sequence can be used to prepare the trans-5-alkenyl-3-vinylbenzoxazepinone and the corresponding trans-5-alkenyl-3-cyclopropylbenzoxazepinone.

One isomer of a compound of formula I may display superior activity compared with the other. Thus, all four of the following stereochemistries are considered to be a part of the present invention. ##STR26##

When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. Lett. 1995, 36, 8937-8940. In addition, separation may be achieved by selective cystallization, optionally in the presence of a chiral acid or base thereby forming a chiral salt.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: anal. for combustion analysis, "g" for gram or grams, HRMS for high resolution mass spectrometry, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "mmol" for millimole or millimoles, "h" for hour or hours, "HPLC" for high performance liquid chromatography, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "TLC" for thin layer chromatography.

For further clarification of the stereochemistry, in compounds with stereochemistry designated as "rel-(3S,5S)" the 3-substituent is cis to the 5-trifluoromethyl group while in compounds with stereochemistry designated as "rel-(3R,5S)" the 3-substituent is trans to the 5-trifluoromethyl group.

Example 1 ##STR27## Preparation of 5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 1-(5-Chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone

1-(2-Amino-5-chlorophenyl)-2,2-trifluoroethanone (see U.S. Pat. No. 5,519,021)(22.4 g, 100 mmol), trityl chloride (30.0 g, 107 mmol), triethylamine (11.6 g, 115 mmol) and 4-(dimethylamino)pyridine (0.5 g, 4 mmol) were dissolved in DMF (50 mL) and held 14 h at 60° C. The resulting slurry was cooled to room temperature, diluted with 20 mL water and filtered to give 35.9 g (77%) of the title compound.

Part B: Preparation of 6-Amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol

To a -30° solution of 1.4 g of 1-butyne in 30 mL of dry THF was added dropwise over 5 min, 7.5 mL of a 1.6 M solution of n-butyllithium in hexane. The reaction mixture was allowed to warm to 0° and then stirred at this temperature for 30 min after which time 1.4 g of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone was added in one portion. The reaction mixture was stirred at 0° for 30 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated to a pure solid. This material was was dissolved in 20 mL of methanol and treated with 0.370 mL of 12 N aqueous hydrochloric acid for 15 min. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried and evaporated. The residue was dissolved in methanol and after cooling in ice for 1 h, the precipitated me hyl trityl ether was filtered off. After evaporation of the filtrate, crystallization from hexanes afforded 675 mg of the title compound as a crystalline solid.

Part C: Preparation of 5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solition of 167 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.066 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF and was treated at room temperature with 25 mg of 100% sodium hydride for 1.5 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product wes purified by preparative silica gel TLC. (elution with ethel acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 106 mg of the title compound as colorless crystals: mp 167 -168°; Anal. Calcd. for C₁₄ H₁₁ NO₂ ClF₃ : C, 52.93; H, 3.49; N, 4.42. Found: C, 52.73; H, 3.64; N, 4.13.

Example 2 ##STR28## Preparation of rel-(3S,5S)-5-(1-Butynyl)-7-chloro-1,5-dihydro-3-phenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 278 mg of 6-amino-3-chloro-α-(1-butynyl)-α-(trifluoromethyl)benzyl alcohol (Example 1, Part B) in 25 mL of dry ether was added 0.150 mL of dry pyridine and 0.200 mL of α-chlorophenacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 50 mg of potassium iodide and 28 mg of 100% sodium hydride were added and this solution was heated at 60° for 12 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product was subjected to column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3) affording a mixture of diastereomers. These were separated by column chromatography over silica gel (elution with 1% methanol in methylene chloride) and the less polar isomer (27 mg) was crystallized from hexane to give 13 mg of the title compound as colorless crystals: mp 198-199°; HRMS Calcd. for C₂₀ H₁₆ NO₂ ClF₃ (M+H)⁺ : 394.082166. Found: 394.080316.

Example 3 ##STR29## Preparation of 7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 6-Amino-3-chloro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 3.06 g (45 mmol) of isopropylacetylene in 90 mL of dry THF was added dropwise over 5 min, 25 mL of a 1.6 M solution of n-butyllithium in hexane (40 mmol). After 30 min at 0°, a solution of 9.3 g of 1-(5-chloro-2-triphenylmethylamiio)phenyl-2,2,2-trifluoroethanone (Example 1, Part A) in 40 mL of dry THF was added dropwise over 5 min. The eaction mixture was stirred at 0° for 15 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine, dried, and evaporated to a pure solid. This material was washed dissolved in 100 mL of methanol and treated with 2.0 mL of 12 N aqueous hydrochloric acid for 15 min. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried, and evaporated. The residue was dissolved in 200 mL of methanol and after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, crystallization from 80 mL of hexanes afforded 4.40 g (75.4%) of the title compound as a crystalline solid.

Part B: Preparation of 7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 4.37 g (15 mmol) of 6-amino-3-chloro-α-(isopropylethnyl)-α-(trifluoromethyl)benzyl alcohol in 200 mL of dry ether was added 2.4 mL of dry pyridine and quickly dropwise, 1.40 mL (16 mmol) of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 150 mL of dry DMF and was treated at 0° with 400 mg of 100% sodium hydride (16.7 mmol) for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1.5 h. The reaction mixture was poured onto a mixture of 1.2 L of water and 300 mL of saturated aqueous sodium chloride and this was extracted 3 times with ether. The combined extracts were washed with brine, dried, and evaporated to a solid which was crystallized by dissolving in hot ethyl acetate and adding hexanes. This material was recrystallized from ethyl acetate/hexane to afford 3.125 g of pure title compound as a crystalline solid: mp 183-183.5°; HRMS Calcd. for C₁₅ H₁₄ NO₂ ClF₃ (M+H)⁺ : 332.066516 Found: 332.065892.

Example 4 ##STR30## Preparation of (+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The racemic material from example 3, Part B above was separated by preparative HPLC or a Chiralcel column maintained at ambient temperature with elution with 10% isopropylamine in carbon dioxide at a pressure of 150 Atm. and a flow rate of 2.0 mL/min. The slower moving isomer was collected and crystallized from hexane: mp 135-136°; [α]²⁵ +9.69.

Example 5 ##STR31## Preparation of trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 3-Chloro-6-(triphenylmethyl)amino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 4.5 g (67.55 mmol) of cyclopropylacetylene in 130 mL of dry THF was added dropwise over 5 min, 37.5 mL (60 mmol) of 1.6 M n-butyllithium. The reaction mixture was allowed to warm to 0° over 30 min after which time a solution of 13.95 g (30.0 mmol) of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone (Example 1, Part A) in 50 mL of cry THF was added dropwise over 5 min. The reaction mixture was stirred at 0° for 30 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated to pure title compound as a glassy solid.

Part B: Preparation of trans-6-Amino-3-chloro-α-(2-cyclopropylethenyl)-α-(trifluoromethyl)benzyl alcohol

The reaction product from part A was dissolved in 100 mL of dry THF and treated overnight with 20 mL of a 1 M solution of lithium aluminum hydride in THF. At this time TLC showed incomplete reaction so an aditional 10 mL of 1 M lithium aluminum hydride was added. After 30 min the reaction was quenched by the addition of 0.800 mL of concentrated aqueous ammonium hydroxide. After gas evoution ceased, the mixture was diluted with ether, filtered through celite, and evaporated. The residue was dissolved in 150 mL of methanol and treated with 3.0 mL of 12 N aqueous hydrochloric acid for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extracted twice with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in 100 mL of boiling methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. The filtrate was evaporated to a solid which was suspended in 100 mL of boiling hexane. Pure colorless crystals of the title compound (404 g) were collected from the cooled mixture.

Part C: Preparation of trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred 0° solution of 230 mg of trans-6-amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.140 mL of dry pyridine and 0.075 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 8 mL of dry DMF and was treated at 0° with 24 mg of 100% sodium hydride. After 15 min the cooling bath was removed and stirring was continued at ambient temperature for 3 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The crude product was purified by column chromatiography over silica gel (elution with ethyl acetate/hexanes 1:3) affording efter crystallization from ethyl acetate/hexanes 127 mg of the title compound as colorless crystals: mp 157-158°; HRMS Calcd. for C₁₅ H₁₄ NO₂ ClF₃ (M+H)⁺ : 332.066516. Found: 332.064517.

Example 6 ##STR32## Preparation of rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solition of 291 mg of trans-6-Amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part C.) in 13 mL of dry ether was added 0.180 mL of dry pyridine and 0.120 mL of bromopropionyl bromide. After 1 h, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 40 mg of 100% sodium hydride. After 15 min the cooliing bath was removed and stirring was continued at ambient temperature for 20 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residie was dissolved in a small amount of ethyl acetate, and addition of hexane resulted in the crystallization of 40 mg of the title compound as colorless crystals: mp 171-172°; HRMS: Calcd. for C₁₆ H₁₆ NO₂ ClF₃ (M+H)⁺ : 346.082166. Found: 346.080681. A second crop of slightly less pure product weighed 41 mg.

Example 7 ##STR33## Preparation of 1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of N-(4-Fluorophenyl)-2,2-dimethylpropanamide

To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organiclayer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid.

Part B: Preparation of 1-(2-Amino-5-fluorophenyl)-2,2,2-trifluoroethanone

To an ice-cooled solution o 4.0 g of N-(4-fluorophenyl)-2,2-dimethylpropandamide in 80 mL of dry THF was added dropwise over 30 min 30.8 mL of a 1.6 M solution of n-butyllithium in hexane. After addition was complete, the reaction mixture was stirred an additional 1 h at 0° after which time 5.63 mL of ethyl trifluoroacetate was added quickly dropwise. The cooling bath was removed and the reaction was allowed to proceed at ambient temperature for 40 min. The reaction was quenched by the addition of aqueous ammonium chloride and the react on mixture was partitioned between ether and water. The ether layer was washed with brine, dried and evaporated to 6.29 g of the title compound as an orange oil. The bulk of this material (6.0 g) was dissloved in ethylene glycol dimethyl ether, 30 mL of 6N HCl was added nd the mixture was heated at reflux for 1.5 h. The cooled reaction mixture was diluted with water, and made basic by the addition of solid sodium carbonate. This was extracted with ether, and the combined extacts were dried and evaporated. The residue was pulified by column chromatography over silica gel (elution with 10-20% ethyl acetate in hexanes) affording 2.10 g of the title compound as an orange solid.

Part C: Preparation of 6-Amino-3-fluoro-α-isopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 1.89 mL of isopropylacetylene in 35 mL of dry THF was added dropwise over 5 min, 10.0 mL of 1.6 M n-butyllithium. The reaction mixture was stirred at 0° for 30 min after which time 828 mg of 1-(2-amino-5-fluorophenyl)-2,2,2-trifluoroethanone was added. The reaction mixture was stirred at 0° for 1.25 h after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated. The residue was purified by column chromatography on silica gel (elution wth ethyl acetate/hexanes) affording 220 mg of the title compound as a tan solid.

Part D: 1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred 0° solution of 210 mg of 6-Amino-3-fluoro-α-isopropylethynyl-α-(trifluoromEthyl)benzyl alcohol in 20 mL of dry ether was added 120 mL of dry pyridine and 0.080 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 20 mL of dry DMF and was treated at room temperature with 33 mg of 100% sodium hydride for 30 min. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:2) affording after crystallization from ethyl acetate/hexanes 89 mg of the title compound as colorless crystals: mp 172-173°; Anal. Calcd. for C₁₅ H₁₃ NO₂ F₄ : C, 57.15; H, 4.17; N, 4.44. Found: C, 57.10; H, 3.98; N, 4.21.

Example 8 ##STR34## Preparation of 1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

A solution of 32 mg of 7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2-one in 4 mL of ethanol was stirred under 1 atmosphere of hydrogen in the presence of 5 mg of 10% palladium on carbon for 12 h. Filtration and evaporation afforded a solid material which was recrystallized from ethyl acetate/hexanes to afford 18 mg of the title compound as colorless crystals: HRMS: Calcd. for C₁₅ H₁₈ NO₂ F₄ (M+H)⁺ : 320.127367. Found: 320.127936.

Example 9 ##STR35## Preparation of rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 1,1-dibromo-2-furan-2-yl-ethylene

To a stirred solution of 9.6 g (29 mmol) of carbon tetrabromide in 120 mL of dry me hylene chloride at 0° was added 15.2 g (58 mmol) of tripheiiylphosphine. After 15 min 3.0 mL (22.5 mmol) of triethylamine was added, and after stirring another 5 min at 0°, the reaction mixture was cooled to -780°. At this temperature 1.50 mL (22.5 mmol) of 2-furaldehyde was added quickly dropwise, and after addition was complete, the mixture was stirred a -70° for 30 min. The reaction mixture was poured onto a rapidly stirring saturated solution of sodium bicarbonate in water. The methylene chloride phase was removed and the aqueous layer was extracted with additional methylene chloride. The combined extracts were evaporated to a solid which was stirred in 500 mL of hexanes for 2 h. After filtration, the filtrate was concentrated to a volume of 50 mL and the filtered again to remove precipitated solid. Final evaporation of the filtrate afforded 3.1 g (58%) of the title compound.

Part B: Preparation of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol

To a solution of 2.88 g (11.4 mmol) of 1,1-dibromo-2-furan-2-ylethene in 40 mL of dry THF at -20° was added dropwise over 5 min, 14.25 mL (22.8 mmol) of 1.6 M n-butyllithium. The reaction mixture was allowed to warm to 0° over 30 min at which time a solution of 4.2 g (9.0 mmol) of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone in 12 mL of dry THF was added dropwise over 1 min. The reaction mixture was stirred at 0° for 30 min after which time it was poured onto saturated aqueous ammonium chloride. This mixture was extracted twice with ether and the combined extracts vere washed with brine, dried, and evaporated to 5.6 g of 3-chloro-6-(triphenylmethy)amino-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol is a dark colored solid.

Part C: Preparation of trans-6-Amino-3-chloro-α-(2-furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol

To a stirred solution of 3.35 g of 3-chloro-6-(triphenylmethy)amino-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 25 mL of dry THF was added 6 mL of 1.0 M lithium aluminum hydride in THF. After 1 h the reaction was quenched by the addition of 0.54 mL of concentrated aqueous ammonium hydroxide. After gas evolution ceased, the mixture was diluted with ether, filtered through celite, and evaporated. The residue was dissolved in 30 mL of methanol and treated with 0.70 mL of 12 N aqueous hydrochloric acid for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in metlanol after cooling in ice for 1 h and the precipitated metlyl trityl ether was filtered off. After evaporation of the filtrate, crystallization from hexanes afforded 888 mg of trans-3-chloro-6-amino-α-(furan-2-yl)ethenyl-α-(trifluoromethyl)berzyl alcohol as crystals.

Part D: Preparation of rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred 0° solution of 317 mg of trans-3-chloro-6-amino-α-(furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 0.125 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, fried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 489 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 24 h. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to 350 mg of crude product from which 108 mg of a single isomer could be isolated by crystallization (ethyl acetate/hexanes). This material was purified further on a short silica gel column, and then recrystallized from ethyl acetate/hexanes to give 86 mg of the title compound as colorless crystals: mp 205-206.5°; Anal. Calcd. for C₁₇ H₁₃ NO₃ F₃ Cl: C, 54.93; H, 3.54; N, 3.78. Found: C., 54.83; H, 3.40; N, 3.61.

Example 10 ##STR36## Preparation of trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled soliution of 159 mg of trans-3-chloro-6-amino-α-(furan-2-yl)ethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 9, Part C) in 8 mL of dry ether was added 0.050 mL of dry pyridine and 0.055 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried, and evaporated. The residue was dissolved in 8 mL of dry DMF, 245 mg of cesium carbonate was added, and the resulting heterogeneous mixture gas stirred at room temperature for 1.5 h. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product from which 86 mg of crystalline material was obtained (ethyl aceate/hexanes). This material was purified further on a short silica gel column (elution with ethyl acetate/hexanes 1:1), and then recrystallized from ethyl acetate/hexanes to give 68 mg of title compound: mp 199-200°; Anal. Calcd. for C₁₆ H₁₁ NO₃ F₃ Cl: C, 53.72; H, 3.11; N, 3.93. Found: C, 54.09 H, 3.35; N, 3.83.

Example 11 ##STR37## Preparation of rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 6-Amino-3-chloro-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol

To a stirred solution of 20 g of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol (Example 9, Part B) in 20 mL of methanol was added 0.125 mL of 12 N aqueous hydrochloric acid, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extractec with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the residue was chromatographed over silica gel (elution with hexanes/ethyl acetate 3:1) affording after crystalization from hexane/ethyl acetate 280 mg of the title compound.

Part B: Preparation of rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 265 mg of 6-amino-3-chloro-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.150 mL of dry pyridine and 0.100 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF at 0°, 25 mg of 100% sodium hydride was added, and the resulting mixture was stirred for 15 min at 0° and at room temperature for 30 min. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to a residue which was purified by column chromatography on silica gel (elution with 17-33% ethyl acetate in hexanes) affording after crystallization from ethyl acetale/hexanes 5 mg of the title compound: HRMS: Calcd. for C₁₇ H₁₂ NO₃ ClF₃ (M+H)⁺ : 369.037956. Found: 369.036835.

Example 12 ##STR38## Preparation of 5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 6-Amino-3-chloro-α-butyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 465 mg (1 mmol) of 1-(5-chloro-2-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone in 15 mL of dry THF was added dropwise 2 mmol of n-butylmagnesium chloride in ether. The reaction mixture was stirred at 0° for 30 min after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extractdd twice with ether and the combined extracts were washed with brine, dried, and evaporated to a pure solid. This material was was dissolved in 10 mL of methanol and treated with 0.100 mL of 12 N aqueous hydrochloric acid for 1 h. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried and evaporated. Crystallization from hexanes afforded 195 mg of the title compound as a crystalline solid.

Part B: Preparation of 5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 185 mg of 6-amino-3-chloro-α-butyl-α-(trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of cry pyridine and 0.060 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 8 mL of dry DMF and was treated at room temperature with 40 mg of 100% sodium hydride for 16 h. The reaction was partitioned between ethyl acetate and water and the ethyl acetate layer was washed with brine, dried, and evaporated. The crude product was purified first by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3), and then by preparative silica gel TLC. (elution with 2.5% methanol in methylene chloride) affording 32 mg of the title compound as an amorphous solid: HRMS: Calcd. for C₁₄ H₁₆ NO₂ ClF₃ (M+H)⁺ : 322.082166. Found: 322.080685.

Example 13 ##STR39## Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one. Part A: Preparation of N-trimethylacetyl-3,4-difluoroandlide.

To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl ard extracted with methylene chloride (3×100 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solic (40.68 g theoretical, 92% yield).

Part B: Preparation of N-Trimethylacetyl 5,6-difluoro-2-trifluoroacetylandlide.

To a solution of N-trimethlacetyl-3,4-difluoroandlide (4.0 g, 14.6 mmol) in THF (60 mL) at -78° C. was added dropwise 1.6M nBuLi in hexane (22 mL, 35 nmol) and the resulting reaction mixture was allowed to stir at -78° C. for 1 h. Ethyl trifluoroacetate (4 mL, 33.6 mmol) was added to the reaction mixture and the resulting solution was allowed to stir with warming to room temperature (ice bath removed after the addition of reagent) for 0.5 h. Phe reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part C: Preparation of 5,6-Difluoro-2-trifluoroacetylaniline.

To a solution of the orange oil in dimethoxyethane (15 mL) was added 6N HCl (75 mL) and the resulting mixture was allowed to reflux for 2 h. The reaction mixture was cooled, made basic with solid Na₂ CO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 2110 mg of 5,6-Difluoro-2-trifluoroacetylaniline as a yellcw solid (3285 mg theoretical, 64% yield).

Part D: Preparation of 1-(2,3-difluoro-6-triphenylmethylamino)phenyl-2,2,2-trifluoroethanone

A solution of 500 mg of 5,6(-Difluoro-2-trifluoroacetylaniline, 693 mg of triphenylmethanol, and 8 mg of p-toluenesulfonic acid in 50 mL of toluene was heated a reflux for 3.5 h using a Dean-Stark trap for water separation. After evaporation of the solvent, the residue was purified by column chromatography over silica gel (5% ethylacetate in hexanes as eluent) affording 760 mg of the title compound as a yellow foam.

Part E: Preparation of 6-Amino-2,3-difluoro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 250 mg of isopropylacetylene in 10 mL of dry THF was added dropwise 1.90 mL of a 1.6 M solution of n-butyllithium in hexane. After 30 min at 0°, 450 mg of 1-(2,3-difluoro-6-triphenylmethylamino)phenyl-2,2,2 -trifluoroethanone in 3 mL of dry THF was added quickly dropwise. The reaction mixture was stirred at 0° for 20 min after which time it was poured onto saturated aqueous ammonium chloride. This mixture was extracted twice with ether and the combined extracts were washed with brine dried and evaporated to an orange solid. 248 mg of this material was was dissolved in 5 mL of methanol and treated with 0.05 mL of 12 N aqueous hydrochloric acid for 20 min. The reaction mixture was partitioned between water and ether, and the ether layer was washed with aqueous bicarbonate, brine, dried, and evaporated. The crude product was purified by column chromatography over silica gel (elution with ethyl acetate/hexanes 1:3) affording 81 mg of the title compound.

Part F: Preparation of 6,7-Difluoro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled soliution of 81 mg of 6-Amino-2,3-difluoro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 8 mL of dry ether was added 0.55 mL of dry pyridine and 0.032 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 10 mg of 100% sodium hydride for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1 h. The reaction was quenched with one drop of acetic acid and then the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and this solution vas washed with water and brine, dried and evaporated to a solid which was crystallized from ethyl acetate/hexanes affording 28 mg of the title compound as colorless crystals: mp 192.5-193.5°; HRMS: Calcd. for C₁₅ H₁₃ NO₂ F₅ (M+H)⁺ : 334.086645. Found: 334.084917.

Example 14 ##STR40## Preparation of rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (Example 14a) and rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (Example 14b) Part A: Preparation of 6-Amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To a stirred solution of 3.0 g of 3-Chloro-6-(triphenylmethyl)amino-α-cycloprcpylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 5, Part A) in 30 mL of methanol was added 0.60 mL of 12 N aqueous hydrochloric acid, and this mixture was stirned at ambient temperature for 10 min. The reaction mixture was poured onto aqueous bicarbonate and extracted twice with ether. The combined extracts were washed withh brine, dried, and evaporated. The residue was dissolved in 20 mL of methanol and after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the crude solid was recrystallized from hekanes affording 1.16 g of the title compound as a purple solid.

Part B: Preparation of rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one and rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solition of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-trifluoromethyl)benzyl alcohol in 15 mL of dry ether was added 0.100 mL of dry pyridine and 220 mg of α-bromobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water end brine, dried and evaporated to 300 mg of crude product. This material was subjected to column chromatography over silica gel (elution with 5-25% ethyl acetate in hexares) affording after crystallization from ethyl acetate/hexanes: 115 mg of rel-(3S,5S)-7-chloro-5-cyclopropyletlynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one as colorless crystals: mp 191-1920°; Anal. Calcd. for C₁₈ H₁₇ NO₂ F₃ Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 57.89; H, 4.61; N, 3.60, and 25 mg of rel-(3R,5S)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one: mp 141°; HRMS: Calcd. for C₁₈ H₁₈ NO₂ F₃ Cl (M+H)⁺ : 372.097816. Found: 372.096539.

Example 15 ##STR41## Preparation of rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 290 mg of 6-amino-3-chloro-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol (Example 14, Part A) in 15 mL of dry ether was added 0.100 mL of dry pyridine and 228 mg of α-bromoisobutyryl chloride. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 15 mL of dry DMF, 268 mg of lithium iodide and 978 mg of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was then poured onto water and etracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated. Since TLC. showed the reaction had only gone halfway to completion, the crude product was redissloved in 15 mL of DMF and subjected to the same reaction conditions as above for another 24 h. After the same work-up, the crude product was purified by column chromatography over silica gel (elution with 5-15% ethyl acetate in hexanes) and then recrystallized from ethyl acetate/hexanes to give 45 mg of the title compound as colorless crystals: mp 167°; Anal. Calcd. for C₁₈ H₁₇ NO₂ F₃ Cl: C, 58.15; H, 4.62; N, 3.78. Found: C, 58.11; H, 4.59; N, 3.70.

Example 16 7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7, except that dilsopropylethylamine was used as a base rather than sodium hydride: mp 190-191°; Anal. Calcd. for C₁₈ H₁₇ NO₂ F₃ Cl: C, 5 59.11; H, 3.03; N, 3.84. Found: C, 58.95; H, 3.12; N, 3.33.

Example 17 rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7: mp 181-182.8°; Anal. Calcd. for C₁₆ H₁₅ NO₂ F₃ Cl: C, 55.58; H, 4.37 N, 4.05. Found: C, 55.37; H, 4.39; N, 3.87.

Example 18 7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7: mp 199.5-200.5°; Anal. Calcd. for C₁₅ H₁₁ NO₂ F₃ Cl: C, 54.64; H, 36; N, 4.26. Found: C, 54.46; H, 3.17; N, 4.03.

Example 19 7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 7: mp 168-169°; Anal. Calcd. for C₁₆ H₁₆ NO₂ F₃ Cl: C, 58.72; H, 4.94; N, 4.29. Found: C, 58.68; H, 4.90; N, 4.29.

Example 20 trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 5: mp 148-149°; HRMS: Calcd. for C₁₅ H₁₆ NO₂ F₃ Cl (M+H)⁺ : 334.082166. Found: 334.081071.

Example 21 7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 8: mp 123-130°; Anal. Calcd. for C₁₆ H₂₀ NO₃ F₃ : C, 58.00; H, 6.08; N, 4.24. Found: C, 57.86; H, 5.95; N, 4.12.

Example 22 rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was obtained along with the title compound of Example 23 by a procedure similar to that of Example 7: mp 180-181°; Anal. Calcd. for C₁₇ H₁₅ NO₂ F₃ Cl: C, 57.07; H, 4.24; N, 3.93. Found: C, 56.85; H, 4.04; N, 3.95.

Example 23 rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was obtained along with the title compound of Example 22 by a procedure similar to that of Example 7: mp 129-130°; HRMS. Calcd. for C₁₇ H₁₅ NO₂ F₃ Cl (M+H)⁺ : 358.082166. Found: 358.081980.

Example 24 7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 11 except that sodium hydride rather than cesium carbonate was the base used in the final reaction step: mp 219-221°; HRMS: Calcd. for C₁₇ H₁₁ N₂ O₂ F₃ Cl (M+H)⁺ : 367.046115. Found: 367.046761.

Example 25 trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 9 except that sodium hydride rather than cesium carbonate was the base used in the final reaction step: mp 199-201°; HRMS: Calcd for C₁₇ H₁₃ N₂ O₂ F₃ Cl (M+H)⁺ : 369.061765. Found: 369.060918.

Example 26 trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 5: mp 145-156°.

Example 27 trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepered in a manner similar to the product of Example 5: mp 159-160°; HRMS: Calcd. for C₁₅ H₁₅ NO₂ F₅ (M+H)⁺ : 336.102295. Found: 336.102028.

Example 28 rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 14: mp :169-174°; HRMS: Calcd. for C₁₆ H₃ NO₂ F₃ Cl (M⁺): 343.058691. Found: 343.057486.

Example 29 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a stirred ice-cooled solution of 987 mg of trans-6-amino-3-chloro-α-cyclopropyletheayl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part B) in 50 mL of dry ether was added 0.350 mL of dry pyridine aid 1.66 g of α-bromopropionyl bromide. The cooling bath was removed and then after 30 min at ambient temperature, the reacation mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residte was dissolved in 50 mL of dry DMF, 2.35 g of lithium iodide and 2.3 g of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 3 days. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product. The title compound was obtained by crystallization from ethyl acetate/hexanes, and recrystallization from ethyl acetate afforded 650 mg of pure title corpound: mp 171-172°; HRMS: Calcd. for C₁₆ H₁₆₈ NO₂ F₃ Cl (M+H)⁺ : 346.082166. Found: 346.080681: mp 147-147.5°; HRMS: Calcd. for C₁₇ H₁₈ NO₂ F₃ Cl (M+H)⁺ : 360.097816. Found: 360.097869

Example 30 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 29: mp 165-167°; HRMS: Calcd. for C₁₈ H₁₉ NO₂ F₃ Cl (M+H)⁺ : 374.113467. Found: 374.114742.

Example 31 rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 11 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 214-215°.

Example 32 rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 11 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 169-170°; HRMS: Calcd. for C₁₈ H₁₄ NO₃ F₃ Cl (M+H)⁺ : 384.061431. Found: 384.058632.

Example 33 rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepered in a manner similar to the product of Example 14: mp 219-220°.

Example 34 rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 14: mp 180.4-181.4°.

Example 35 rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound was prepared in a manner similar to the product of Example 6 except that cesium carbonate/lithium iodide rather than sodium hydride was used in the final reaction step: mp 192-193°; HRMS: Calcd. for C₁₆ H₁₅ NO₂ F₅ (M+H)⁺ : 348.102295. Found: 343.102515.

Example 36 (+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 28 in a manner similar to the procedure described in Example 4: mp 145-146°; Anal. Calcd. for C₁₆ H₁₃ NO₂ F₃ Cl C, 55.91; H, 3.81; N, 4.07. Found: C, 55.80; H, 3.75; N, 3.88. [α]²⁵ +94.200.

Example 37 (3S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 18 in a manner similar to the procedure described in Example 4: mp 135-136°; Anal. Calcd. for C₁₅ H₁₁ NO₂ F₃ Cl C, 54.64; H, 3.36; N, 4.26. Found: C, 54.69; H, 3.17; N, 4.00.

Example 38 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 147-147.5°; HRMS: Calcd. for C₁₇ H₁₈ NO₂ F₃ Cl (M+H)⁺ : 360.097816. Found: 360.097869

Example 39 (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 29 in a manner similar to the procedure described in Example 4: mp 175-175.5°; Anal. Calcd. for C₁₆ H₁₅ NO₂ F₃ Cl C, 55.58; H, 4.37; N, 4.05. Found: C, 55.38; H, 4.21; N, 3.83. [α]²⁵ +61.7°.

Example 40 (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 38 in a manner similar to the procedure described in Example 4: mp 163-164°; [α]²⁵ +22.70.

Example 41 rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of 1-(5-Chloro-2-(4-methoxyphenyl)methylamino)phenyl-2,2,2-trifluoroethanone

A mixture of 6.0 g of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone, 3.84 mL of 4methoxybenzyl alcohol, 114 mg of p-toluensulfonic acid, and 25 mL of dry acetonitrile was heated at 80° for 3.5 hr. An additional 0.5 g of 4-methoxybenzyl alcohol was added and heating was continued for another 2 hr. The cooled solutexon was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, and brine, dried and evaporated . This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 8.2 g of 1-(5-chloro-2-(4-methoxyphenyl)methylamino)phenyl-2,2,2-trifluoroethanone as a yellow solid.

Part B: Preparation of 3-Chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol

To an ice-cooled solution of 3.92 g (59.6 mmol) of cyclopropylacetylene in 100 mL of dry THF was added dropwise over 5 min, 33.0 mL (52.4 mmol) of 1.6 M n-butyllithium. The reaction mixture was allowed to stir at 0° for 30 min after which time it was cooled to -40° and a solution of 8.20 g (23.85 mmol) of 1-(5-chloro-2-(4-methoxyphenyl)methylamino)phenyl-2,2,2-trifluoroethanone in 20 mL of dry THF was added dropwise over 5 min. The reaction mixture was stirred at -40° for 2.0 h after which time it was quenched with saturated aqueous ammonium chloride and poured onto water. This mixture was extracted twice with ether and the combined extracts were washed with brine, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-20% ethyl acetate in hexanes) affording 6.0 g of the title compound as a solid.

Part C: 3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 1.64 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 1.13 g of the title compound as a mixture of diastereomers.

Part D: rel-(3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 1.13 g of 3-(2-bromoethyl)-7-chloro-5-cycloproprolethynyl-1,5-dihydro-1,5-(4-methoxybenzyl)-5-(trifluoromethy )-4,1-benzoxazepin-2(3H)-one in 50 mL of acetonitrile was added 25 mL of water and 5.7 g of ceric ammonium nitrate. After 30 min, the reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (270 mg) was the title compound.

Part E: rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 409 mg (1.8 mmol) of 2-nitrophenylselenocyanate in 5.0 mL of THF was added 16 mL of ethanol and 90 mg of sodium borohydride. After stirring 1 h, a solution of 260 mg of rel-3S,5S)-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 8 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 2 h, at which time an additional 20 mg of sodium borohydride was added and stirring was continued for an additional 2 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 130 mg of the title compound as a pure solid: HRMS: Calcd. for C₁₇ H₁₄ NO₂ F₃ Cl (M+H)⁺ : 354.0508. Found: 354.0487.

Example 42 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one Part A: Preparation of trans-3-Chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethenyl-.alpha.-(trifluoromethyl)benzyl alcohol

To a solution of 1.23 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol from Example 41, Part B) in 12 mL of dry THF was added 15 mL of a 1M solution of lithium aluminum hydride in THF. The reaction mixture was stirred at ambient temperature for 3 days after which time it was quenched by the dropwise addition of 1.1 mL of concentrated aqueous ammonium hydroxide. This mixture was poured onto water and extracted with ether. The extracts were washed with brine, dried and evaporated to afford 1.15 g of the title compound as a pure oil.

Part B: trans-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 1.65 g of trans-3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethenyl-.alpha.-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-33% ethyl acetate in hexanes) affording the title compound. A later eluting fraction (160 mg) proved to be uncyclized material, This was combined with 300 mg of cesium carbonate in 4 mL of DMF and stirred overnight at room temperature. The reaction mixture was poured onto water and extracted with ether. the organic layer was washed with brine, dried and evaporated to give when combined with the product obtained from the column chromatography 750 mg of the title compound as a mixture of diastereomers.

Part C: rel-(3S,5S)-trans-3-(2-Bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 750 mg of trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 35 mL of acetonitrile was added 18 mL of water and 3.78 g of ceric ammonium nitrate. After 20 min, the reaction mixture was partitioned between eater and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (162 mg) was the title compound.

Part D: rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a room temperature solution of 238 mg (1.05 mmol) of 2-nitrophenylselenocyanate in 3.0 mL of THF was added 9 mL of ethanol and 66 mg of sodium borchydride. After stirring 1.5 h, a solution of 153 mg of rel-(3S,5S)-trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 5 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 32 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 73 mg of the title compound as a pure solid which can be recrystallized from ethanol-hexanes: mp 165.5-166.5°; HRMS Calcd. for C₁₇ H₁₆ NO₂ F₃ Cl (M+H)⁺ : 358.082166. Found: 358.081658.

Example 43 rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 71 mg of rel-(3S,5S)-7-chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 41) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and the filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 65 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 36 mg: mp 192-192.50; HRMS: Calcd. for C₁₈ H₁₄ NO₂ F₃ Cl (M-H)⁻ : 368.0665. Found: 368.0657.

Example 44 rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

To a solution of 73 mg of rel-(3S,5S)-trans-7-chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 42) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and he filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 47 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 31 mg: mp 143-144°; HRMS: Calcd. for C₁₈ H₁₆ NO₂ F₃ Cl (M-H)⁻ : 370.0822. Found: 370.0801.

Example 45 rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 41: mp 171-172°; HRMS: Calcd. for C₁₇ H₁₃ NO₂ F₅ (M+H)⁺ : 358.0866. Found: 358.0881.

Example 46 rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared from the product of Example 45 in a manner similar to the procedure described in Example 43: mp 222-222.5°; HRMS Calcd. for C₁₈ H₁₅ NO₂ F₅ (M+H)⁺ : 373.1023. Found: 372.1013.

Example 47 rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 41: Calcd. for C₁₇ H₁₂ NO₂ F₄ (M-H)⁻ : 338.0804. Found: 338.0815.

Example 48 rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 184-185°; HRMS: Calcd. for C₁₆ H₁₄ NO₂ F₄ (M+H)⁺ : 328.0961. Found: 328.0955.

Example 49 rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 186°; Anal. Calcd. for C₁₇ H₁₅ NO₂ F₄ : C, 59.83; H, 4,43; N. 4.10. Found: C, 59.56; H. 4.37; N, 4.02.

Example 50 rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 180-182°; HRMS: Calcd. for C₁₆ H₁₆ NO₂ F₄ (M+H)⁺ : 330.1117. Found: 330.1118.

Example 51 rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 148-149°; HRMS: Calcd. for C₁₇ H₁₈₃ NO₂ F₄ (M+H)⁺ : 344.1274. Found: 344.1265.

Example 52 rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 252-253°.

Example 53 rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 14: mp 201-202°; HRMS: Calcd. for C₁₈ H₁₇ NO₄ F₃ (M⁺): 367.1031. Found: 367.1041.

Example 54 rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 236-237°; HRMS: Calcd. for C₁₇ H₁₇ NO₄ F₃ (M+H)⁺ : 356.1110. Found: 356.1110.

Example 55 rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one

The title compound can be prepared in a manner similar to the procedure described in Example 29: mp 188-190°; HRMS: Calcd. for C₁₈ H₁₉ NO₄ F₃ (M+H)⁺ : 370.1267. Found: 370.1269.

                                      TABLE 1                                      __________________________________________________________________________       #STR42##                                                                        -                                                                           Ex. #                                                                              G     R.sup.2    R.sup.a                                                                               m.p. (° C.)                                                                   Mass Spec                                    __________________________________________________________________________      1  7-Cl  C.tbd.C-Et H      167-168                                               2 7-Cl (S)-C.tbd.C-Et (S)-Ph 198-199 394.08                                    3 7-Cl C.tbd.C-iPr H   183-183.5 332.07                                        4 (+) 7-Cl (S)-C.tbd.C-iPr H 135-136                                           5 7-Cl trans-C═C-cycPr H 157-158 332.06                                    6 7-Cl trans-C═C-cycPr (S)-CH.sub.3 171-172 346.08                         7 7-F C.tbd.C-iPr H 172-173                                                    8 7-F 3-methylbutyl H  320.13                                                  9 7-Cl (S)-trans-C═C-2-furan (S)-CH.sub.3   205-206.5                     10 7-Cl trans-C═C-2-furan H 199-200                                        11 7-Cl (S)-C.tbd.C-2-furan (S)-CH.sub.3  369.04                               12 7-Cl butyl H  322.08                                                        13 6,7-diF C.tbd.C-iPr H 192.5-193.5 334.08                                    14a 7-Cl (S)-C.tbd.C-cycPr (S)-CH.sub.3 191-92                                 14b 7-Cl (S)-C.tbd.C-cycPr (R)-CH.sub.3 141 372.10                             15 7-Cl (S)-C.tbd.C-CycPr (S)-iPr 167                                          16 7-Cl C.tbd.C-Ph H 190-191                                                   17 7-Cl (S)-C.tbd.C-iPr (S)-CH.sub.3   181-182.8                               18 7-Cl C.tbd.C-cycPr H 199.5-200.5                                            19 7-Cl C.tbd.C-iPr H 168-169                                                  20 7-Cl trans-C═C-cycPr H 148-149                                          21 7-CH.sub.3 O C.tbd.C-cycPr H 129-130                                        22 7-Cl (S)-C.tbd.C-cycPr (S)-Et 180-181                                       23 7-Cl (S)-C.tbd.C-cycPr (R)-Et 129-130 358.08                                24 7-Cl C.tbd.C-3-pyridyl H 219-221 367.05                                     25 7-Cl trans-C═C-3-pyridyl H 199-201 369.06                               26 7-F trans-C═C-iPr H 145-156                                             27 6,7-F trans-C═C-iPr H 159-160 336.10                                    28 7-Cl (S)-C.tbd.C-cycPr (S)-CH.sub.3 169-174 343.06                          29 7-Cl (S)-trans-C═C-cycPr (S)-CH.sub.3   147-147.5 360.10                                                 30 7-Cl (S)-trans-C═C-cycPr (S)-Pr                                        165-167 374.11                                 31 7-Cl (S)-C.tbd.C-3-furan (S)-CH.sub.3 214-215                               32 7-Cl (S)-C.tbd.C-3-furan (S)-Et 169-170 384.06                              33 6,7-F (S)-C.tbd.C-cycPr (S)-CH.sub.3 219-220                                34 6,7-F (S)-C.tbd.C-cycPr (S)-Et 180.4-181.4                                  35 6,7-F (S)-C.tbd.C-cycPr (S)-CH.sub.3 192-193 348.10                         36 (+) 7-Cl (S)-C.tbd.C-cycPr (S)-CH.sub.3 145-146                             37 7-Cl (S)-C.tbd.C-cycPr H 135-136                                            38 7-Cl (S)-trans-C═C-cycPr (S)-Et   147-147.5 360.10                      39 (+) 7-Cl (S)-trans-C═C-cycPr (S)-CH.sub.3   175-175.5                   40 (+) 7-Cl (S)-trans-C═C-cycPr (S)-Et 163-164                             41 7-Cl (S)-C.tbd.C-cycPr (S)-CH═CH.sub.2  354.05                          42 7-Cl (S)-trans-C═C-cycPr (S)-CH═CH.sub.2 165.5-166.5 358.08                                          43 7-Cl (S)-C.tbd.C-cycPr (S)-cycPr                                           192-192.5 368.07                               44 7-Cl (S)-trans-C═C-cycPr (S)-cycPr 143-144 370.08                       45 6,7-F (S)-C.tbd.C-cycPr (S)-CH═CH.sub.2 171-172 358.09                  46 6,7-F (S)-C.tbd.C-cycPr (S)-cycPr   222-222.5 372.10                        47 7-F (S)-C.tbd.C-cycPr (S)-CH═CH.sub.2  338.08                           48 7-F (S)-C.tbd.C-cycPr (S)-CH.sub.3 184-185 328.10                           49 7-F (S)-C.tbd.C-cycPr (S)-Et 186                                            50 7-F (S)-trans-C═C-cycPr (S)-CH.sub.3 180-182 330.11                     51 7-F (S)-trans-C═C-cycPr (S)-Et 148-149 344.13                           52 6,7-(CH.sub.2).sub.2 O (S)-C.tbd.C-cycPr (S)-CH.sub.3 252-252                                                53 6,7-(CH.sub.2).sub.2 O (S)-C.tbd.C-c                                       ycPr (S)-Et 201-202 367.10                     54 6,7-(CH.sub.2).sub.2 O (S)-trans-C═C-cycPr (S)-CH.sub.3 236-237                                         356.11                                         55 6,7-(CH.sub.2).sub.2 O (S)-trans-C═C-cycPr (S)-Et 188-190             __________________________________________________________________________                                       370.13                                        *Unless otherwise noted, stereochemistry is (+/-).                       

Tables 2 and 3 show representative compounds of the present invention. Each formula shown at the start of Table 2 and 3 is intended to be paired with each entry in the table which follows.

                  TABLE 2                                                          ______________________________________                                           #STR43##                                                                         #STR44##                                                                           #STR45##                                                                           #STR46##                                                                         #STR47##                                                                         #STR48##                                                                         #STR49##                                                                         #STR50##                                                                         #STR51##                                                    -                    Ex. # G          R.sup.1                                                 R.sup.2                                                      ______________________________________                                         201     6-Cl         CF.sub.3                                                                              n-butyl                                              202 6-Cl CF.sub.3 C.tbd.C-Et                                                   203 6-Cl CF.sub.3 C.tbd.C-iPr                                                  204 6-Cl CF.sub.3 C.tbd.C-cycPr                                                205 6-Cl CF.sub.3 C.tbd.C-2-pyridyl                                            206 6-Cl CF.sub.3 C.tbd.C-3-pyridyl                                            207 6-Cl CF.sub.3 C.tbd.C-2-furanyl                                            208 6-Cl CF.sub.3 C.tbd.C-3-furanyl                                            209 6-Cl CF.sub.3 C.tbd.C-2-thienyl                                            210 6-Cl CF.sub.3 C.tbd.C-3-thienyl                                            211 6-Cl CF.sub.3 CH═CH-Et                                                 212 6-Cl CF.sub.3 CH═CH-iPr                                                213 6-Cl CF.sub.3 CH═CH-cycPr                                              214 6-Cl CF.sub.3 CH═CH-2-pyridyl                                          215 6-Cl CF.sub.3 CH═CH-3-pyridyl                                          216 6-Cl CF.sub.3 CH═CH-2-furanyl                                          217 6-Cl CF.sub.3 CH═CH-3-furanyl                                          218 6-Cl CF.sub.3 CH═CH-2-thienyl                                          219 6-Cl CF.sub.3 CH═CH-3-thienyl                                          220 6-Cl CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                     221 6-Cl CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                                 222 6-Cl CF.sub.3 CH.sub.2 CH═CH-cycPr                                     223 6-Cl CF.sub.3 CH.sub.2 CH═CH-2-furanyl                                 224 6-Cl CF.sub.3 CH═CHCH.sub.2 -cycPr                                     225 6-Cl CF.sub.3 CH═CHCH.sub.2 -2-furanyl                                 226 7-Cl CF.sub.3 n-butyl                                                      227 7-Cl CF.sub.3 C.tbd.C-Et                                                   228 7-Cl CF.sub.3 C.tbd.C-iPr                                                  229 7-Cl CF.sub.3 C.tbd.C-cycPr                                                230 7-Cl CF.sub.3 C.tbd.C-2-pyridyl                                            231 7-Cl CF.sub.3 C.tbd.C-3-pyridyl                                            232 7-Cl CF.sub.3 C.tbd.C-2-furanyl                                            233 7-Cl CF.sub.3 C.tbd.C-3-furanyl                                            234 7-Cl CF.sub.3 C.tbd.C-2-thienyl                                            235 7-Cl CF.sub.3 C.tbd.C-3-thienyl                                            236 7-Cl CF.sub.3 CH═CH-Et                                                 237 7-Cl CF.sub.3 CH═CH-iPr                                                238 7-Cl CF.sub.3 CH═CH-cycPr                                              239 7-Cl CF.sub.3 CH═CH-2-pyridyl                                          240 7-Cl CF.sub.3 CH═CH-3-pyridyl                                          241 7-Cl CF.sub.3 CH═CH-2-furanyl                                          242 7-Cl CF.sub.3 CH═CH-3-furanyl                                          243 7-Cl CF.sub.3 CH═CH-2-thienyl                                          244 7-Cl CF.sub.3 CH═CH-3-thienyl                                          245 7-Cl CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                     246 7-Cl CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                                 247 7-Cl CF.sub.3 CH.sub.2 CH═CH-cycPr                                     248 7-Cl CF.sub.3 CH.sub.2 CH═CH-2-furanyl                                 249 7-Cl CF.sub.3 CH═CHCH.sub.2 -cycPr                                     250 7-Cl CF.sub.3 CH═CHCH.sub.2 -2-furanyl                                 251 6-F CF.sub.3 n-butyl                                                       252 6-F CF.sub.3 C.tbd.C-Et                                                    253 6-F CF.sub.3 C.tbd.C-iPr                                                   254 6-F CF.sub.3 C.tbd.C-cycPr                                                 255 6-F CF.sub.3 C.tbd.C-2-pyridyl                                             256 6-F CF.sub.3 C.tbd.C-3-pyridyl                                             257 6-F CF.sub.3 C.tbd.C-2-furanyl                                             258 6-F CF.sub.3 C.tbd.C-3-furanyl                                             259 6-F CF.sub.3 C.tbd.C-2-thienyl                                             260 6-F CF.sub.3 C.tbd.C-3-thienyl                                             261 6-F CF.sub.3 CH═CH-Et                                                  262 6-F CF.sub.3 CH═CH-iPr                                                 263 6-F CF.sub.3 CH═CH-cycPr                                               264 6-F CF.sub.3 CH═CH-2-pyridyl                                           265 6-F CF.sub.3 CH═CH-3-pyridyl                                           266 6-F CF.sub.3 CH═CH-2-furanyl                                           267 6-F CF.sub.3 CH═CH-3-furanyl                                           268 6-F CF.sub.3 CH═CH-2-thienyl                                           269 6-F CF.sub.3 CH═CH-3-thienyl                                           270 6-F CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                      271 6-F CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                                  272 6-F CF.sub.3 CH.sub.2 CH═CH-cycPr                                      273 6-F CF.sub.3 CH.sub.2 CH═CH-2-furanyl                                  274 6-F CF.sub.3 CH═CHCH.sub.2 -cycPr                                      275 6-F CF.sub.3 CH═CHCH.sub.2 -2-furanyl                                  276 7-F CF.sub.3 n-butyl                                                       277 7-F CF.sub.3 C.tbd.C-Et                                                    278 7-F CF.sub.3 C.tbd.C-iPr                                                   279 7-F CF.sub.3 C.tbd.C-cycPr                                                 280 7-F CF.sub.3 C.tbd.C-2-pyridyl                                             281 7-F CF.sub.3 C.tbd.C-3-pyridyl                                             282 7-F CF.sub.3 C.tbd.C-2-furanyl                                             283 7-F CF.sub.3 C.tbd.C-3-furanyl                                             284 7-F CF.sub.3 C.tbd.C-2-thienyl                                             285 7-F CF.sub.3 C.tbd.C-3-thienyl                                             286 7-F CF.sub.3 CH═CH-Et                                                  287 7-F CF.sub.3 CH═CH-iPr                                                 288 7-F CF.sub.3 CH═CH-cycPr                                               289 7-F CF.sub.3 CH═CH-2-pyridyl                                           290 7-F CF.sub.3 CH═CH-3-pyridyl                                           291 7-F CF.sub.3 CH═CH-2-furanyl                                           292 7-F CF.sub.3 CH═CH-3-furanyl                                           293 7-F CF.sub.3 CH═CH-2-thienyl                                           294 7-F CF.sub.3 CH═CH-3-thienyl                                           295 7-F CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                      296 7-F CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                                  297 7-F CF.sub.3 CH.sub.2 CH═CH-cycPr                                      298 7-F CF.sub.3 CH.sub.2 CH═CH-2-furanyl                                  299 7-F CF.sub.3 CH═CHCH.sub.2 -cycPr                                      300 7-F CF.sub.3 CH═CHCH.sub.2 -2-furanyl                                  301 6,7-diCl CF.sub.3 n-butyl                                                  302 6,7-diCl CF.sub.3 C.tbd.C-Et                                               303 6,7-diCl CF.sub.3 C.tbd.C-iPr                                              304 6,7-diCl CF.sub.3 C.tbd.C-cycPr                                            305 6,7-diCl CF.sub.3 C.tbd.C-2-pyridyl                                        306 6,7-diCl CF.sub.3 C.tbd.C-3-pyridyl                                        307 6,7-diCl CF.sub.3 C.tbd.C-2-furanyl                                        308 6,7-diCl CF.sub.3 C.tbd.C-3-furanyl                                        309 6,7-diCl CF.sub.3 C.tbd.C-2-thienyl                                        310 6,7-diCl CF.sub.3 C.tbd.C-3-thienyl                                        311 6,7-diCl CF.sub.3 CH═CH-Et                                             312 6,7-diCl CF.sub.3 CH═CH-iPr                                            313 6,7-diCl CF.sub.3 CH═CH-cycPr                                          314 6,7-diCl CF.sub.3 CH═CH-2-pyridyl                                      315 6,7-diCl CF.sub.3 CH═CH-3-pyridyl                                      316 6,7-diCl CF.sub.3 CH═CH-2-furanyl                                      317 6,7-diCl CF.sub.3 CH═CH-3-furanyl                                      318 6,7-diCl CF.sub.3 CH═CH-2-thienyl                                      319 6,7-diCl CF.sub.3 CH═CH-3-thienyl                                      320 6,7-diCl CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                 321 6,7-diCl CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                             322 6,7-diCl CF.sub.3 CH.sub.2 CH═CH-cycPr                                 323 6,7-diCl CF.sub.3 CH.sub.2 CH═CH-2-furanyl                             324 6,7-diCl CF.sub.3 CH═CHCH.sub.2 -cycPr                                 325 6,7-diCl CF.sub.3 CH═CHCH.sub.2 -2-furanyl                             326 6,7-diF CF.sub.3 n-butyl                                                   327 6,7-diF CF.sub.3 C.tbd.C-Et                                                328 6,7-diF CF.sub.3 C.tbd.C-iPr                                               329 6,7-diF CF.sub.3 C.tbd.C-cycPr                                             330 6,7-diF CF.sub.3 C.tbd.C-2-pyridyl                                         331 6,7-diF CF.sub.3 C.tbd.C-3-pyridyl                                         332 6,7-diF CF.sub.3 C.tbd.C-2-furanyl                                         333 6,7-diF CF.sub.3 C.tbd.C-3-furanyl                                         334 6,7-diF CF.sub.3 C.tbd.C-2-thienyl                                         335 6,7-diF CF.sub.3 C.tbd.C-3-thienyl                                         336 6,7-diF CF.sub.3 CH═CH-Et                                              337 6,7-diF CF.sub.3 CH═CH-iPr                                             338 6,7-diF CF.sub.3 CH═CH-cycPr                                           339 6,7-diF CF.sub.3 CH═CH-2-pyridyl                                       340 6,7-diF CF.sub.3 CH═CH-3-pyridyl                                       341 6,7-diF CF.sub.3 CH═CH-2-furanyl                                       342 6,7-diF CF.sub.3 CH═CH-3-furanyl                                       343 6,7-diF CF.sub.3 CH═CH-2-thienyl                                       344 6,7-diF CF.sub.3 CH═CH-3-thienyl                                       345 6,7-diF CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                  346 6,7-diF CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                              347 6,7-diF CF.sub.3 CH.sub.2 CH═CH-cycPr                                  348 6,7-diF CF.sub.3 CH.sub.2 CH═CH-2-furanyl                              349 6,7-diF CF.sub.3 CH═CHCH.sub.2 -cycPr                                  350 6,7-diF CF.sub.3 CH═CHCH.sub.2 -2-furanyl                              351 6-Cl, 7-F CF.sub.3 n-butyl                                                 352 6-Cl, 7-F CF.sub.3 C.tbd.C-Et                                              353 6-Cl, 7-F CF.sub.3 C.tbd.C-iPr                                             354 6-Cl, 7-F CF.sub.3 C.tbd.C-cycPr                                           355 6-Cl, 7-F CF.sub.3 C.tbd.C-2-pyridyl                                       356 6-Cl, 7-F CF.sub.3 C.tbd.C-3-pyridyl                                       357 6-Cl, 7-F CF.sub.3 C.tbd.C-2-furanyl                                       358 6-Cl, 7-F CF.sub.3 C.tbd.C-3-furanyl                                       359 6-Cl, 7-F CF.sub.3 C.tbd.C-2-thienyl                                       360 6-Cl, 7-F CF.sub.3 C.tbd.C-3-thienyl                                       361 6-Cl, 7-F CF.sub.3 CH═CH-Et                                            362 6-Cl, 7-F CF.sub.3 CH═CH-iPr                                           363 6-Cl, 7-F CF.sub.3 CH═CH-cycPr                                         364 6-Cl, 7-F CF.sub.3 CH═CH-2-pyridyl                                     365 6-Cl, 7-F CF.sub.3 CH═CH-3-pyridyl                                     366 6-Cl, 7-F CF.sub.3 CH═CH-2-furanyl                                     367 6-Cl, 7-F CF.sub.3 CH═CH-3-furanyl                                     368 6-Cl, 7-F CF.sub.3 CH═CH-2-thienyl                                     369 6-Cl, 7-F CF.sub.3 CH═CH-3-thienyl                                     370 6-Cl, 7-F CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                371 6-Cl, 7-F CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                            372 6-Cl, 7-F CF.sub.3 CH.sub.2 CH═CH-cycPr                                373 6-Cl, 7-F CF.sub.3 CH.sub.2 CH═CH-2-furanyl                            374 6-Cl, 7-F CF.sub.3 CH═CHCH.sub.2 -cycPr                                375 6-Cl, 7-F CF.sub.3 CH═CHCH.sub.2 -2-furanyl                            376 6-F, 7-Cl CF.sub.3 n-butyl                                                 377 6-F, 7-Cl CF.sub.3 C.tbd.C-Et                                              378 6-F, 7-Cl CF.sub.3 C.tbd.C-iPr                                             379 6-F, 7-Cl CF.sub.3 C.tbd.C-cycPr                                           380 6-F, 7-Cl CF.sub.3 C.tbd.C-2-pyridyl                                       381 6-F, 7-Cl CF.sub.3 C.tbd.C-3-pyridyl                                       382 6-F, 7-Cl CF.sub.3 C.tbd.C-2-furanyl                                       383 6-F, 7-Cl CF.sub.3 C.tbd.C-3-furanyl                                       384 6-F, 7-Cl CF.sub.3 C.tbd.C-2-thienyl                                       385 6-F, 7-Cl CF.sub.3 C.tbd.C-3-thienyl                                       386 6-F, 7-Cl CF.sub.3 CH═CH-Et                                            387 6-F, 7-Cl CF.sub.3 CH═CH-iPr                                           388 6-F, 7-Cl CF.sub.3 CH═CH-cycPr                                         389 6-F, 7-Cl CF.sub.3 CH═CH-2-pyridyl                                     390 6-F, 7-Cl CF.sub.3 CH═CH-3-pyridyl                                     391 6-F, 7-Cl CF.sub.3 CH═CH-2-furanyl                                     392 6-F, 7-Cl CF.sub.3 CH═CH-3-furanyl                                     393 6-F, 7-Cl CF.sub.3 CH═CH-2-thienyl                                     394 6-F, 7-Cl CF.sub.3 CH═CH-3-thienyl                                     395 6-F, 7-Cl CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                                396 6-F, 7-Cl CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                            397 6-F, 7-Cl CF.sub.3 CH.sub.2 CH═CH-cycPr                                398 6-F, 7-Cl CF.sub.3 CH.sub.2 CH═CH-2-furanyl                            399 6-F, 7-Cl CF.sub.3 CH═CHCH.sub.2 -cycPr                                400 6-F, 7-Cl CF.sub.3 CH═CHCH.sub.2 -2-furanyl                            401 7-CH.sub.3 CF.sub.3 n-butyl                                                402 7-CH.sub.3 CF.sub.3 C.tbd.C-Et                                             403 7-CH.sub.3 CF.sub.3 C.tbd.C-iPr                                            404 7-CH.sub.3 CF.sub.3 C.tbd.C-cycPr                                          405 7-CH.sub.3 CF.sub.3 C.tbd.C-2-pyridyl                                      406 7-CH.sub.3 CF.sub.3 C.tbd.C-3-pyridyl                                      407 7-CH.sub.3 CF.sub.3 C.tbd.C-2-furanyl                                      408 7-CH.sub.3 CF.sub.3 C.tbd.C-3-furanyl                                      409 7-CH.sub.3 CF.sub.3 C.tbd.C-2-thienyl                                      410 7-CH.sub.3 CF.sub.3 C.tbd.C-3-thienyl                                      411 7-CH.sub.3 CF.sub.3 CH═CH-Et                                           412 7-CH.sub.3 CF.sub.3 CH═CH-iPr                                          413 7-CH.sub.3 CF.sub.3 CH═CH-cycPr                                        414 7-CH.sub.3 CF.sub.3 CH═CH-2-pyridyl                                    415 7-CH.sub.3 CF.sub.3 CH═CH-3-pyridyl                                    416 7-CH.sub.3 CF.sub.3 CH═CH-2-furanyl                                    417 7-CH.sub.3 CF.sub.3 CH═CH-3-furanyi                                    418 7-CH.sub.3 CF.sub.3 CH═CH-2-thienyl                                    419 7-CH.sub.3 CF.sub.3 CH═CH-3-thienyl                                    420 7-CH.sub.3 CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                               421 7-CH.sub.3 CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                           422 7-CH.sub.3 CF.sub.3 CH.sub.2 CH═CH-cycPr                               423 7-CH.sub.3 CF.sub.3 CH.sub.2 CH═CH-2-furanyl                           424 7-CH.sub.3 CF.sub.3 CH═CHCH.sub.2 -cycPr                               425 7-CH.sub.3 CF.sub.3 CH═CHCH.sub.2 -2-furanyl                           426 7-OCH.sub.3 CF.sub.3 n-butyl                                               427 7-OCH.sub.3 CF.sub.3 C.tbd.C-Et                                            428 7-OCH.sub.3 CF.sub.3 C.tbd.C-iPr                                           429 7-OCH.sub.3 CF.sub.3 C.tbd.C-cycPr                                         430 7-OCH.sub.3 CF.sub.3 C.tbd.C-2-pyridyl                                     431 7-OCH.sub.3 CF.sub.3 C.tbd.C-3-pyrldyl                                     432 7-OCH.sub.3 CF.sub.3 C.tbd.C-2-furanyl                                     433 7-OCH.sub.3 CF.sub.3 C.tbd.C-3-furanyl                                     434 7-OCH.sub.3 CF.sub.3 C.tbd.C-2-thienyl                                     435 7-OCH.sub.3 CF.sub.3 C.tbd.C-3-thienyl                                     436 7-OCH.sub.3 CF.sub.3 CH═CH-Et                                          437 7-OCH.sub.3 CF.sub.3 CH═CH-iPr                                         438 7-OCH.sub.3 CF.sub.3 CH═CH-cycPr                                       439 7-OCH.sub.3 CF.sub.3 CH═CH-2-pyridyl                                   440 7-OCH.sub.3 CF.sub.3 CH═CH-3-pyridyl                                   441 7-OCH.sub.3 CF.sub.3 CH═CH-2-furanyl                                   442 7-OCH.sub.3 CF.sub.3 CH═CH-3-furanyl                                   443 7-OCH.sub.3 CF.sub.3 CH═CH-2-thienyl                                   444 7-OCH.sub.3 CF.sub.3 CH═CH-3-thienyl                                   445 7-OCH.sub.3 CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                              446 7-OCH.sub.3 CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                          447 7-OCH.sub.3 CF.sub.3 CH.sub.2 CH═CH-cycPr                              448 7-OCH.sub.3 CF.sub.3 CH.sub.2 CH═CH-2-furanyl                          449 7-OCH.sub.3 CF.sub.3 CH═CHCH.sub.2 -cycPr                              450 7-OCH.sub.3 CF.sub.3 CH═CHCH.sub.2 -2-furanyl                          451 7-pyrazol-6-yl CF.sub.3 n-butyl                                            452 7-pyrazol-6-yl CF.sub.3 C.tbd.C-Et                                         453 7-pyrazol-6-yl CF.sub.3 C.tbd.C-iPr                                        454 7-pyrazol-6-yl CF.sub.3 C.tbd.C-cycPr                                      455 7-pyrazol-6-yl CF.sub.3 C.tbd.C-2-pyridyl                                  456 7-pyrazol-6-yl CF.sub.3 C.tbd.C-3-pyridyl                                  457 7-pyrazol-6-yl CF.sub.3 C.tbd.C-2-furanyl                                  458 7-pyrazol-6-yl CF.sub.3 C.tbd.C-3-furanyl                                  459 7-pyrazol-6-yl CF.sub.3 C.tbd.C-2-thienyl                                  460 7-pyrazol-6-yl CF.sub.3 C.tbd.C-3-thienyl                                  461 7-pyrazol-6-yl CF.sub.3 CH═CH-Et                                       462 7-pyrazol-6-yl CF.sub.3 CH═CH-iPr                                      463 7-pyrazol-6-yl CF.sub.3 CH═CH-cycPr                                    464 7-pyrazol-6-yl CF.sub.3 CH═CH-2-pyridyl                                465 7-pyrazol-6-yl CF.sub.3 CH═CH-3-pyridyl                                466 7-pyrazol-6-yl CF.sub.3 CH═CH-2-furanyl                                467 7-pyrazol-6-yl CF.sub.3 CH═CH-3-furanyl                                468 7-pyrazol-6-yl CF.sub.3 CH═CH-2-thienyl                                469 7-pyrazol-6-yl CF.sub.3 CH═CH-3-thienyl                                470 7-pyrazol-6-yl CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                           471 7-pyrazol-6-yl CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                       472 7-pyrazol-6-yl CF.sub.3 CH.sub.2 CH═CH-cycPr                           473 7-pyrazol-6-yl CF.sub.3 CH.sub.2 CH═CH-2-furanyl                       474 7-pyrazol-6-yl CF.sub.3 CH═CHCH.sub.2 -cycPr                           475 7-pyrazol-6-yl CF.sub.3 CH═CHCH.sub.2 -2-furanyl                       476 6,7-OCH.sub.2 O-- CF.sub.3 n-butyl                                         477 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-Et                                      478 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-iPr                                     479 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-cycPr                                   480 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-pyridyl                               481 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-pyridyl                               482 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-furanyl                               483 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-furanyl                               484 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-thienyl                               485 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-thienyl                               486 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-Et                                    487 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-iPr                                   488 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-cycPr                                 489 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-2-pyridyl                             490 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-3-pyridyl                             491 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-2-furanyl                             492 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-3-furanyl                             493 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-2-thienyl                             494 6,7-OCH.sub.2 O-- CF.sub.3 CH═CH-3-thienyl                             495 6,7-OCH.sub.2 O-- CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                        496 6,7-OCH.sub.2 O-- CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                    497 6,7-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH═CH-cycPr                        498 6,7-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH═CH-2-furanyl                    499 6,7-OCH.sub.2 O-- CF.sub.3 CH═CHCH.sub.2 -cycPr                        500 6,7-OCH.sub.2 O-- CF.sub.3 CH═CHCH.sub.2 -2-furanyl                    501 7-CONH.sub.2 CF.sub.3 n-butyl                                              502 7-CONH.sub.2 CF.sub.3 C.tbd.C-Et                                           503 7-CONH.sub.2 CF.sub.3 C.tbd.C-iPr                                          504 7-CONH.sub.2 CF.sub.3 C.tbd.C-cycPr                                        505 7-CONH.sub.2 CF.sub.3 C.tbd.C-2-pyridyl                                    506 7-CONH.sub.2 CF.sub.3 C.tbd.C-3-pyridyl                                    507 7-CONH.sub.2 CF.sub.3 C.tbd.C-2-furanyl                                    508 7-CONH.sub.2 CF.sub.3 C.tbd.C-3-furanyl                                    509 7-CONH.sub.2 CF.sub.3 C.tbd.C-2-thienyl                                    510 7-CONH.sub.2 CF.sub.3 C.tbd.C-3-thienyl                                    511 7-CONH.sub.2 CF.sub.3 CH═CH-Et                                         512 7-CONH.sub.2 CF.sub.3 CH═CH-iPr                                        513 7-CONH.sub.2 CF.sub.3 CH═CH-cycPr                                      514 7-CONH.sub.2 CF.sub.3 CH═CH-2-pyridyl                                  515 7-CONH.sub.2 CF.sub.3 CH═CH-3-pyridyl                                  516 7-CONH.sub.2 CF.sub.3 CH═CH-2-furanyl                                  517 7-CONH.sub.2 CF.sub.3 CH═CH-3-furanyl                                  518 7-CONH.sub.2 CF.sub.3 CH═CH-2-thienyl                                  519 7-CONH.sub.2 CF.sub.3 CH═CH-3-thienyl                                  520 7-CONH.sub.2 CF.sub.3 CH.sub.2 --C.tbd.C-cycPr                             521 7-CONH.sub.2 CF.sub.3 CH.sub.2 --C.tbd.C-2-furanyl                         522 7-CONH.sub.2 CF.sub.3 CH.sub.2 CH═CH-cycPr                             523 7-CONH.sub.2 CF.sub.3 CH.sub.2 CH═CH-2-furanyl                         524 7-CONH.sub.2 CF.sub.3 CH═CHCH.sub.2 -cycPr                             525 7-CONH.sub.2 CF.sub.3 CH═CHCH.sub.2 -2-furanyl                         526 6-Cl C.sub.2 F.sub.5 n-butyl                                               527 6-Cl C.sub.2 F.sub.5 C.tbd.C-Et                                            528 6-Cl C.sub.2 F.sub.5 C.tbd.C-iPr                                           529 6-Cl C.sub.2 F.sub.5 C.tbd.C-cycPr                                         530 6-Cl C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                     531 6-Cl C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                     532 6-Cl C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                     533 6-Cl C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                     534 6-Cl C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                     535 6-Cl C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                     536 6-Cl C.sub.2 F.sub.5 CH═CH-Et                                          537 6-Cl C.sub.2 F.sub.5 CH═CH-iPr                                         538 6-Cl C.sub.2 F.sub.5 CH═CH-cycPr                                       539 6-Cl C.sub.2 F.sub.5 CH═CH-2-pyridyl                                   540 6-Cl C.sub.2 F.sub.5 CH═CH-3-pyridyl                                   541 6-Cl C.sub.2 F.sub.5 CH═CH-2-furanyl                                   542 6-Cl C.sub.2 F.sub.5 CH═CH-3-furanyl                                   543 6-Cl C.sub.2 F.sub.5 CH═CH-2-thienyl                                   544 6-Cl C.sub.2 F.sub.5 CH═CH-3-thienyl                                   545 6-Cl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                              546 6-Cl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                          547 6-Cl C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                              548 6-Cl C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                          549 6-Cl C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                              550 6-Cl C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                          551 7-Cl C.sub.2 F.sub.5 n-butyl                                               552 7-Cl C.sub.2 F.sub.5 C.tbd.C-Et                                            553 7-Cl C.sub.2 F.sub.5 C.tbd.C-iPr                                           554 7-Cl C.sub.2 F.sub.5 C.tbd.C-cycPr                                         555 7-Cl C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                     556 7-Cl C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                     557 7-Cl C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                     558 7-Cl C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                     559 7-Cl C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                     560 7-Cl C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                     561 7-Cl C.sub.2 F.sub.5 CH═CH-Et                                          562 7-Cl C.sub.2 F.sub.5 CH═CH-iPr                                         563 7-Cl C.sub.2 F.sub.5 CH═CH-cycPr                                       564 7-Cl C.sub.2 F.sub.5 CH═CH-2-pyridyl                                   565 7-Cl C.sub.2 F.sub.5 CH═CH-3-pyridyl                                   566 7-Cl C.sub.2 F.sub.5 CH═CH-2-furanyl                                   567 7-Cl C.sub.2 F.sub.5 CH═CH-3-furanyl                                   568 7-Cl C.sub.2 F.sub.5 CH═CH-2-thienyl                                   569 7-Cl C.sub.2 F.sub.5 CH═CH-3-thienyl                                   570 7-Cl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                              571 7-Cl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                          572 7-Cl C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                              573 7-Cl C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                          574 7-Cl C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                              575 7-Cl C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                          576 6-F C.sub.2 F.sub.5 n-butyl                                                577 6-F C.sub.2 F.sub.5 C.tbd.C-Et                                             578 6-F C.sub.2 F.sub.5 C.tbd.C-iPr                                            579 6-F C.sub.2 F.sub.5 C.tbd.C-cycPr                                          580 6-F C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                      581 6-F C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                      582 6-F C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                      583 6-F C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                      584 6-F C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                      585 6-F C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                      586 6-F C.sub.2 F.sub.5 CH═CH-Et                                           587 6-F C.sub.2 F.sub.5 CH═CH-iPr                                          588 6-F C.sub.2 F.sub.5 CH═CH-cycPr                                        589 6-F C.sub.2 F.sub.5 CH═CH-2-pyridyl                                    590 6-F C.sub.2 F.sub.5 CH═CH-3-pyridyl                                    591 6-F C.sub.2 F.sub.5 CH═CH-2-furanyl                                    592 6-F C.sub.2 F.sub.5 CH═CH-3-furanyl                                    593 6-F C.sub.2 F.sub.5 CH═CH-2-thienyl                                    594 6-F C.sub.2 F.sub.5 CH═CH-3-thienyl                                    595 6-F C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                               596 6-F C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                           597 6-F C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                               598 6-F C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                           599 6-F C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                               600 6-F C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                           601 7-F C.sub.2 F.sub.5 n-butyl                                                602 7-F C.sub.2 F.sub.5 C.tbd.C-Et                                             603 7-F C.sub.2 F.sub.5 C.tbd.C-iPr                                            604 7-F C.sub.2 F.sub.5 C.tbd.C-cycPr                                          605 7-F C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                      606 7-F C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                      607 7-F C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                      608 7-F C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                      609 7-F C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                      610 7-F C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                      611 7-F C.sub.2 F.sub.5 CH═CH-Et                                           612 7-F C.sub.2 F.sub.5 CH═CH-iPr                                          613 7-F C.sub.2 F.sub.5 CH═CH-cycPr                                        614 7-F C.sub.2 F.sub.5 CH═CH-2-pyridyl                                    615 7-F C.sub.2 F.sub.5 CH═CH-3-pyridyl                                    616 7-F C.sub.2 F.sub.5 CH═CH-2-furanyl                                    617 7-F C.sub.2 F.sub.5 CH═CH-3-furanyl                                    618 7-F C.sub.2 F.sub.5 CH═CH-2-thienyl                                    619 7-F C.sub.2 F.sub.5 CH═CH-3-thienyl                                    620 7-F C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                               621 7-F C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                           622 7-F C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                               623 7-F C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                           624 7-F C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                               625 7-F C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                           626 6,7-diCl C.sub.2 F.sub.5 n-butyl                                           627 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-Et                                        628 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-iPr                                       629 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-cycPr                                     630 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                 631 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                 632 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                 633 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                 634 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                 635 6,7-diCl C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                 636 6,7-diCl C.sub.2 F.sub.5 CH═CH-Et                                      637 6,7-diCl C.sub.2 F.sub.5 CH═CH-iPr                                     638 6,7-diCl C.sub.2 F.sub.5 CH═CH-cycPr                                   639 6,7-diCl C.sub.2 F.sub.5 CH═CH-2-pyridyl                               640 6,7-diCl C.sub.2 F.sub.5 CH═CH-3-pyridyl                               641 6,7-diCl C.sub.2 F.sub.5 CH═CH-2-furanyl                               642 6,7-diCl C.sub.2 F.sub.5 CH═CH-3-furanyl                               643 6,7-diCl C.sub.2 F.sub.5 CH═CH-2-thienyl                               644 6,7-diCl C.sub.2 F.sub.5 CH═CH-3-thienyl                               645 6,7-diCl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                          646 6,7-diCl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                      647 6,7-diCl C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                          648 6,7-diCl C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                      649 6,7-diCl C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                          650 6,7-diCl C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                      651 6,7-diF C.sub.2 F.sub.5 n-butyl                                            652 6,7-diF C.sub.2 F.sub.5 C.tbd.C-Et                                         653 6,7-diF C.sub.2 F.sub.5 C.tbd.C-iPr                                        654 6,7-diF C.sub.2 F.sub.5 C.tbd.C-cycPr                                      655 6,7-diF C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                  656 6,7-diF C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                  657 6,7-diF C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                  658 6,7-diF C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                  659 6,7-diF C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                  660 6,7-diF C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                  661 6,7-diF C.sub.2 F.sub.5 CH═CH-Et                                       662 6,7-diF C.sub.2 F.sub.5 CH═CH-iPr                                      663 6,7-diF C.sub.2 F.sub.5 CH═CH-cycPr                                    664 6,7-diF C.sub.2 F.sub.5 CH═CH-2-pyridyl                                665 6,7-diF C.sub.2 F.sub.5 CH═CH-3-pyridyl                                666 6,7-diF C.sub.2 F.sub.5 CH═CH-2-furanyl                                667 6,7-diF C.sub.2 F.sub.5 CH═CH-3-furanyl                                668 6,7-diF C.sub.2 F.sub.5 CH═CH-2-thienyl                                669 6,7-diF C.sub.2 F.sub.5 CH═CH-3-thienyl                                670 6,7-diF C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                           671 6,7-diF C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                       672 6,7-diF C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                           673 6,7-diF C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                       674 6,7-diF C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                           675 6,7-diF C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                       676 6-Cl, 7-F C.sub.2 F.sub.5 n-butyl                                          677 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-Et                                       678 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-iPr                                      679 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-cycPr                                    680 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                681 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                682 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                683 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                684 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                685 6-Cl, 7-F C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                686 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-Et                                     687 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-iPr                                    688 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-cycPr                                  689 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-2-pyridyl                              690 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-3-pyridyl                              691 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-2-furanyl                              692 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-3-furanyl                              693 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-2-thienyl                              694 6-Cl, 7-F C.sub.2 F.sub.5 CH═CH-3-thienyl                              695 6-Cl, 7-F C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                         696 6-Cl, 7-F C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                     697 6-Cl, 7-F C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                         698 6-Cl, 7-F C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                     699 6-Cl, 7-F C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                         700 6-Cl, 7-F C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                     701 6-F, 7-Cl C.sub.2 F.sub.5 n-butyl                                          702 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-Et                                       703 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-iPr                                      704 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-cycPr                                    705 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                                706 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                                707 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-2-furanyl                                708 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-3-furanyl                                709 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-2-thienyl                                710 6-F, 7-Cl C.sub.2 F.sub.5 C.tbd.C-3-thienyl                                711 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-Et                                     712 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-iPr                                    713 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-cycPr                                  714 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-2-pyridyl                              715 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-3-pyridyl                              716 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-2-furanyl                              717 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-3-furanyl                              718 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-2-thienyl                              719 6-F, 7-Cl C.sub.2 F.sub.5 CH═CH-3-thienyl                              720 6-F, 7-Cl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                         721 6-F, 7-Cl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                     722 6-F, 7-Cl C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                         723 6-F, 7-Cl C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                     724 6-F, 7-Cl C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                         725 6-F, 7-Cl C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                     726 7-CH.sub.3 C.sub.2 F.sub.5 n-butyl                                         727 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-Et                                      728 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-iPr                                     729 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-cycPr                                   730 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                               731 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                               732 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-2-furanyl                               733 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-3-furanyl                               734 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-2-thienyl                               735 7-CH.sub.3 C.sub.2 F.sub.5 C.tbd.C-3-thienyl                               736 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-Et                                    737 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-iPr                                   738 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-cycPr                                 739 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-2-pyridyl                             740 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-3-pyridyl                             741 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-2-furanyl                             742 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-3-furanyl                             743 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-2-thienyl                             744 7-CH.sub.3 C.sub.2 F.sub.5 CH═CH-3-thienyl                             745 7-CH.sub.3 C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                        746 7-CH.sub.3 C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                    747 7-CH.sub.3 C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                        748 7-CH.sub.3 C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                    749 7-CH.sub.3 C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                        750 7-CH.sub.3 C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                    751 7-OCH.sub.3 C.sub.2 F.sub.5 n-butyl                                        752 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-Et                                     753 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-iPr                                    754 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-cycPr                                  755 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                              756 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                              757 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-2-furanyl                              758 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-3-furanyl                              759 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-2-thienyl                              760 7-OCH.sub.3 C.sub.2 F.sub.5 C.tbd.C-3-thienyl                              761 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-Et                                   762 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-iPr                                  763 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-cycPr                                764 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-2-pyridyl                            765 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-3-pyridyl                            766 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-2-furanyl                            767 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-3-furanyl                            768 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-2-thienyl                            769 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CH-3-thienyl                            770 7-OCH.sub.3 C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                       771 7-OCH.sub.3 C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                   772 7-OCH.sub.3 C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                       773 7-OCH.sub.3 C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                   774 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                       775 7-OCH.sub.3 C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                   776 7-pyrazol-6-yl C.sub.2 F.sub.5 n-butyl                                     777 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-Et                                  778 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-iPr                                 779 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-cycPr                               780 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                           781 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                           782 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-2-furanyl                           783 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-3-furanyl                           784 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-2-thienyl                           785 7-pyrazol-6-yl C.sub.2 F.sub.5 C.tbd.C-3-thienyl                           786 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-Et                                787 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-iPr                               788 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-cycPr                             789 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-2-pyridyl                         790 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-3-pyridyl                         791 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-2-furanyl                         792 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-3-furanyl                         793 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-2-thienyl                         794 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CH-3-thienyl                         795 7-pyrazol-6-yl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                    796 7-pyrazol-6-yl C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                                           797 7-pyrazol-6-yl C.sub.2 F.sub.5 CH.sub.2                                   CH═CH-cycPr                                      798 7-pyrazol-6-yl C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                                           799 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CHC                                 H.sub.2 -cycPr                                       800 7-pyrazol-6-yl C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                                           801 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5                                         n-butyl                                              802 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-Et                               803 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-iPr                              804 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-cycPr                            805 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                        806 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                        807 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-2-furanyl                        808 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-3-furanyl                        809 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-2-thienyl                        810 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 C.tbd.C-3-thienyl                        811 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-Et                             812 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-iPr                            813 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-cycPr                          814 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-2-pyridyl                      815 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-3-pyridyl                      816 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-2-furanyl                      817 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-3-furanyl                      818 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-2-thienyl                      819 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CH-3-thienyl                      820 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                 821 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                                        822 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5                                         CH.sub.2 CH═CH-cycPr                             823 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                                        824 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5                                         CH═CHCH.sub.2 -cycPr                             825 6,7-OCH.sub.2 O-- C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                                        826 7-CONH.sub.2 C.sub.2 F.sub.5 n-butyl                                       827 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-Et                                    828 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-iPr        829 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-cycPr                                 830 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-2-pyridyl                             831 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-3-pyridyl                             832 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-2-furanyl                             833 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-3-furanyl                             834 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-2-thienyl                             835 7-CONH.sub.2 C.sub.2 F.sub.5 C.tbd.C-3-thienyl                             836 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-Et                                  837 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-iPr                                 838 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-cycPr                               839 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-2-pyridyl                           840 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-3-pyridyl                           841 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-2-furanyl                           842 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-3-furanyl                           843 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-2-thienyl                           844 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CH-3-thienyl                           845 7-CONH.sub.2 C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-cycPr                      846 7-CONH.sub.2 C.sub.2 F.sub.5 CH.sub.2 --C.tbd.C-2-furanyl                  847 7-CONH.sub.2 C.sub.2 F.sub.5 CH.sub.2 CH═CH-cycPr                      848 7-CONH.sub.2 C.sub.2 F.sub.5 CH.sub.2 CH═CH-2-furanyl                  849 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CHCH.sub.2 -cycPr                      850 7-CONH.sub.2 C.sub.2 F.sub.5 CH═CHCH.sub.2 -2-furanyl                  851 6-Cl cycPr n-butyl                                                         852 6-Cl cycPr C.tbd.C-Et                                                      853 6-Cl cycPr C.tbd.C-iPr                                                     854 6-Cl cycPr C.tbd.C-cycPr                                                   855 6-Cl cycPr C.tbd.C-2-pyridyl                                               856 6-Cl cycPr C.tbd.C-3-pyridyl                                               857 6-Cl cycPr C.tbd.C-2-furanyl                                               858 6-Cl cycPr C.tbd.C-3-furanyl                                               859 6-Cl cycPr C.tbd.C-2-thienyl                                               860 6-Cl cycPr C.tbd.C-3-thienyl                                               861 6-Cl cycPr CH═CH-Et                                                    862 6-Cl cycPr CH═CH-iPr                                                   863 6-Cl cycPr CH═CH-cycPr                                                 864 6-Cl cycPr CH═CH-2-pyridyl                                             865 6-Cl cycPr CH═CH-3-pyridyl                                             866 6-Cl cycPr CH═CH-2-furanyl                                             867 6-Cl cycPr CH═CH-3-furanyl                                             868 6-Cl cycPr CH═CH-2-thienyl                                             869 6-Cl cycPr CH═CH-3-thienyl                                             870 6-Cl cycPr CH.sub.2 --C.tbd.C-cycPr                                        871 6-Cl cycPr CH.sub.2 --C.tbd.C-2-furanyl                                    872 6-Cl cycPr CH.sub.2 CH═CH-cycPr                                        873 6-Cl cycPr CH.sub.2 CH═CH-2-furanyl                                    874 6-Cl cycPr CH═CHCH.sub.2 -cycPr                                        875 6-Cl cycPr CH═CHCH.sub.2 -2-furanyl                                    876 7-Cl cycPr n-butyl                                                         877 7-Cl cycPr C.tbd.C-Et                                                      878 7-Cl cycPr C.tbd.C-iPr                                                     879 7-Cl cycPr C.tbd.C-cycPr                                                   880 7-Cl cycPr C.tbd.C-2-pyridyl                                               881 7-Cl cycPr C.tbd.C-3-pyridyl                                               882 7-Cl cycPr C.tbd.C-2-furanyl                                               883 7-Cl cycPr C.tbd.C-3-furanyl                                               884 7-Cl cycPr C.tbd.C-2-thienyl                                               885 7-Cl cycPr C.tbd.C-3-thienyl                                               886 7-Cl cycPr CH═CH-Et                                                    887 7-Cl cycPr CH═CH-iPr                                                   888 7-Cl cycPr CH═CH-cycPr                                                 889 7-Cl cycPr CH═CH-2-pyridyl                                             890 7-Cl cycPr CH═CH-3-pyridyl                                             891 7-Cl cycPr CH═CH-2-furanyl                                             892 7-Cl cycPr CH═CH-3-furanyl                                             893 7-Cl cycPr CH═CH-2-thienyl                                             894 7-Cl cycPr CH═CH-3-thienyl                                             895 7-Cl cycPr CH.sub.2 --C.tbd.C-cycPr                                        896 7-Cl cycPr CH.sub.2 --C.tbd.C-2-furanyl                                    897 7-Cl cycPr CH.sub.2 CH═CH-cycPr                                        898 7-Cl cycPr CH.sub.2 CH═CH-2-furanyl                                    899 7-Cl cycPr CH═CHCH.sub.2 -cycPr                                        900 7-Cl cycPr CH═CHCH.sub.2 -2-furanyl                                    901 6-F cycPr n-butyl                                                          902 6-F cycPr C.tbd.C-Et                                                       903 6-F cycPr C.tbd.C-iPr                                                      904 6-F cycPr C.tbd.C-cycPr                                                    905 6-F cycPr C.tbd.C-2-pyridyl                                                906 6-F cycPr C.tbd.C-3-pyridyl                                                907 6-F cycPr C.tbd.C-2-furanyl                                                908 6-F cycPr C.tbd.C-3-furanyl                                                909 6-F cycPr C.tbd.C-2-thienyl                                                910 6-F cycPr C.tbd.C-3-thienyl                                                911 6-F cycPr CH═CH-Et                                                     912 6-F cycPr CH═CH-iPr                                                    913 6-F cycPr CH═CH-cycPr                                                  914 6-F cycPr CH═CH-2-pyridyl                                              915 6-F cycPr CH═CH-3-pyridyl                                              916 6-F cycPr CH═CH-2-furanyl                                              917 6-F cycPr CH═CH-3-furanyl                                              918 6-F cycPr CH═CH-2-thienyl                                              919 6-F cycPr CH═CH-3-thienyl                                              920 6-F cycPr CH.sub.2 --C.tbd.C-cycPr                                         921 6-F cycPr CH.sub.2 --C.tbd.C-2-furanyl                                     922 6-F cycPr CH.sub.2 CH═CH-cycPr                                         923 6-F cycPr CH.sub.2 CH═CH-2-furanyl                                     924 6-F cycPr CH═CHCH.sub.2 -cycPr                                         925 6-F cycPr CH═CHCH.sub.2 -2-furanyl                                     926 7-F cycPr n-butyl                                                          927 7-F cycPr C.tbd.C-Et                                                       928 7-F cycPr C.tbd.C-iPr                                                      929 7-F cycPr C.tbd.C-cycPr                                                    930 7-F cycPr C.tbd.C-2-pyridyl                                                931 7-F cycPr C.tbd.C-3-pyridyl                                                932 7-F cycPr C.tbd.C-2-furanyl                                                933 7-F cycPr C.tbd.C-3-furanyl                                                934 7-F cycPr C.tbd.C-2-thienyl                                                935 7-F cycPr C.tbd.C-3-thienyl                                                936 7-F cycPr CH═CH-Et                                                     937 7-F cycPr CH═CH-iPr                                                    938 7-F cycPr CH═CH-cycPr                                                  939 7-F cycPr CH═CH-2-pyridyl                                              940 7-F cycPr CH═CH-3-pyridyl                                              941 7-F cycPr CH═CH-2-furanyl                                              942 7-F cycPr CH═CH-3-furanyl                                              943 7-F cycPr CH═CH-2-thienyl                                              944 7-F cycPr CH═CH-3-thienyl                                              945 7-F cycPr CH.sub.2 --C.tbd.C-cycPr                                         946 7-F cycPr CH.sub.2 --C.tbd.C-2-furanyl                                     947 7-F cycPr CH.sub.2 CH═CH-cycPr                                         948 7-F cycPr CH.sub.2 CH═CH-2-furanyl                                     949 7-F cycPr CH═CHCH.sub.2 -cycPr                                         950 7-F cycPr CH═CHCH.sub.2 -2-furanyl                                     951 6,7-diCl cycPr n-butyl                                                     952 6,7-diCl cycPr C.tbd.C-Et                                                  953 6,7-diCl cycPr C.tbd.C-iPr                                                 954 6,7-diCl cycPr C.tbd.C-cycPr                                               955 6,7-diCl cycPr C.tbd.C-2-pyridyl                                           956 6,7-diCl cycPr C.tbd.C-3-pyridyl                                           957 6,7-diCl cycPr C.tbd.C-2-furanyl                                           958 6,7-diCl cycPr C.tbd.C-3-furanyl                                           959 6,7-diCl cycPr C.tbd.C-2-thienyl                                           960 6,7-diCl cycPr C.tbd.C-3-thienyl                                           961 6,7-diCl cycPr CH═CH-Et                                                962 6,7-diCl cycPr CH═CH-iPr                                               963 6,7-diCl cycPr CH═CH-cycPr                                             964 6,7-diCl cycPr CH═CH-2-pyridyl                                         965 6,7-diCl cycPr CH═CH-3-pyridyl                                         966 6,7-diCl cycPr CH═CH-2-furanyl                                         967 6,7-diCl cycPr CH═CH-3-furanyl                                         968 6,7-diCl cycPr CH═CH-2-thienyl                                         969 6,7-diCl cycPr CH═CH-3-thienyl                                         970 6,7-diCl cycPr CH.sub.2 --C.tbd.C-cycPr                                    971 6,7-diCl cycPr CH.sub.2 --C.tbd.C-2-furanyl                                972 6,7-diCl cycPr CH.sub.2 CH═CH-cycPr                                    973 6,7-diCl cycPr CH.sub.2 CH═CH-2-furanyl                                974 6,7-diCl cycPr CH═CHCH.sub.2 -cycPr                                    975 6,7-diCl cycPr CH═CHCH.sub.2 -2-furanyl                                976 6,7-diF cycPr n-butyl                                                      977 6,7-diF cycPr C.tbd.C-Et                                                   978 6,7-diF cycPr C.tbd.C-iPr                                                  979 6,7-diF cycPr C.tbd.C-cycPr                                                980 6,7-diF cycPr C.tbd.C-2-pyridyl                                            981 6,7-diF cycPr C.tbd.C-3-pyridyl                                            982 6,7-diF cycPr C.tbd.C-2-furanyl                                            983 6,7-diF cycPr C.tbd.C-3-furanyl                                            984 6,7-diF cycPr C.tbd.C-2-thienyl                                            985 6,7-diF cycPr C.tbd.C-3-thienyl                                            986 6,7-diF cycPr CH═CH-Et                                                 987 6,7-diF cycPr CH═CH-iPr                                                988 6,7-diF cycPr CH═CH-cycPr                                              989 6,7-diF cycPr CH═CH-2-pyridyl                                          990 6,7-diF cycPr CH═CH-3-pyridyl                                          991 6,7-diF cycPr CH═CH-2-furanyl                                          992 6,7-diF cycPr CH═CH-3-furanyl                                          993 6,7-diF cycPr CH═CH-2-thienyl                                          994 6,7-diF cycPr CH═CH-3-thienyl                                          995 6,7-diF cycPr CH.sub.2 --C.tbd.C-cycPr                                     996 6,7-diF cycPr CH.sub.2 --C.tbd.C-2-furanyl                                 997 6,7-diF cycPr CH.sub.2 CH═CH-cycPr                                     998 6,7-diF cycPr CH.sub.2 CH═CH-2-furanyl                                 999 6,7-diF cycPr CH═CHCH.sub.2 -cycPr                                     1000  6,7-diF cycPr CH═CHCH.sub.2 -2-furanyl                               1001  6-Cl, 7-F cycPr n-butyl                                                  1002  6-Cl, 7-F cycPr C.tbd.C-Et                                               1003  6-Cl, 7-F cycPr C.tbd.C-iPr                                              1004  6-Cl, 7-F cycPr C.tbd.C-cycPr                                            1005  6-Cl, 7-F cycPr C.tbd.C-2-pyridyl                                        1006  6-Cl, 7-F cycPr C.tbd.C-3-pyridyl                                        1007  6-Cl, 7-F cycPr C.tbd.C-2-furanyl                                        1008  6-Cl, 7-F cycPr C.tbd.C-3-furanyl                                        1009  6-Cl, 7-F cycPr C.tbd.C-2-thienyl                                        1010  6-Cl, 7-F cycPr C.tbd.C-3-thienyl                                        1011  6-Cl, 7-F cycPr CH═CH-Et                                             1012  6-Cl, 7-F cycPr CH═CH-iPr                                            1013  6-Cl, 7-F cycPr CH═CH-cycPr                                          1014  6-Cl, 7-F cycPr CH═CH-2-pyridyl                                      1015  6-Cl, 7-F cycPr CH═CH-3-pyridyl                                      1016  6-Cl, 7-F cycPr CH═CH-2-furanyl                                      1017  6-Cl, 7-F cycPr CH═CH-3-furanyl                                      1018  6-Cl, 7-F cycPr CH═CH-2-thienyl                                      1019  6-Cl, 7-F cycPr CH═CH-3-thienyl                                      1020  6-Cl, 7-F cycPr CH.sub.2 --C.tbd.C-cycPr                                 1021  6-Cl, 7-F cycPr CH.sub.2 --C.tbd.C-2-furanyl                             1022  6-Cl, 7-F cycPr CH.sub.2 CH═CH-cycPr                                 1023  6-Cl, 7-F cycPr CH.sub.2 CH═CH-2-furanyl                             1024  6-Cl, 7-F cycPr CH═CHCH.sub.2 -cycPr                                 1025  6-Cl, 7-F cycPr CH═CHCH.sub.2 -2-furanyl                             1026  6-F, 7-Cl cycPr n-butyl                                                  1027  6-F, 7-Cl cycPr C.tbd.C-Et                                               1028  6-F, 7-Cl cycPr C.tbd.C-iPr                                              1029  6-F, 7-Cl cycPr C.tbd.C-cycPr                                            1030  6-F, 7-Cl cycPr C.tbd.C-2-pyridyl                                        1031  6-F, 7-Cl cycPr C.tbd.C-3-pyridyl                                        1032  6-F, 7-Cl cycPr C.tbd.C-2-furanyl                                        1033  6-F, 7-Cl cycPr C.tbd.C-3-furanyl                                        1034  6-F, 7-Cl cycPr C.tbd.C-2-thienyl                                        1035  6-F, 7-Cl cycPr C.tbd.C-3-thienyl                                        1036  6-F, 7-Cl cycPr CH═CH-Et                                             1037  6-F, 7-Cl cycPr CH═CH-iPr                                            1038  6-F, 7-Cl cycPr CH═CH-cycPr                                          1039  6-F, 7-Cl cycPr CH═CH-2-pyridyl                                      1040  6-F, 7-Cl cycPr CH═CH-3-pyridyl                                      1041  6-F, 7-Cl cycPr CH═CH-2-furanyl                                      1042  6-F, 7-Cl cycPr CH═CH-3-furanyl                                      1043  6-F, 7-Cl cycPr CH═CH-2-thienyl                                      1044  6-F, 7-Cl cycPr CH═CH-3-thienyl                                      1045  6-F, 7-Cl cycPr CH.sub.2 --C.tbd.C-cycPr                                 1046  6-F, 7-Cl cycPr CH.sub.2 --C.tbd.C-2-furanyl                             1047  6-F, 7-Cl cycPr CH.sub.2 CH═CH-cycPr                                 1048  6-F, 7-Cl cycPr CH.sub.2 CH═CH-2-furanyl                             1049  6-F, 7-Cl cycPr CH═CHCH.sub.2 -cycPr                                 1050  6-F, 7-Cl cycPr CH═CHCH.sub.2 -2-furanyl                             1051  7-CH.sub.3 cycPr n-butyl                                                 1052  7-CH.sub.3 cycPr C.tbd.C-Et                                              1053  7-CH.sub.3 cycPr C.tbd.C-iPr                                             1054  7-CH.sub.3 cycPr C.tbd.C-cycPr                                           1055  7-CH.sub.3 cycPr C.tbd.C-2-pyridyl                                       1056  7-CH.sub.3 cycPr C.tbd.C-3-pyridyl                                       1057  7-CH.sub.3 cycPr C.tbd.C-2-furanyl                                       1058  7-CH.sub.3 cycPr C.tbd.C-3-furanyl                                       1059  7-CH.sub.3 cycPr C.tbd.C-2-thienyl                                       1060  7-CH.sub.3 cycPr C.tbd.C-3-thienyl                                       1061  7-CH.sub.3 cycPr CH═CH-Et                                            1062  7-CH.sub.3 cycPr CH═CH-iPr                                           1063  7-CH.sub.3 cycPr CH═CH-cycPr                                         1064  7-CH.sub.3 cycPr CH═CH-2-pyridyl                                     1065  7-CH.sub.3 cycPr CH═CH-3-pyridyl                                     1066  7-CH.sub.3 cycPr CH═CH-2-furanyl                                     1067  7-CH.sub.3 cycPr CH═CH-3-furanyl                                     1068  7-CH.sub.3 cycPr CH═CH-2-thienyl                                     1069  7-CH.sub.3 cycPr CH═CH-3-thienyl                                     1070  7-CH.sub.3 cycPr CH.sub.2 --C.tbd.C-cycPr                                1071  7-CH.sub.3 cycPr CH.sub.2 --C.tbd.C-2-furanyl                            1072  7-CH.sub.3 cycPr CH.sub.2 CH═CH-cycPr                                1073  7-CH.sub.3 cycPr CH.sub.2 CH═CH-2-furanyl                            1074  7-CH.sub.3 cycPr CH═CHCH.sub.2 -cycPr                                1075  7-CH.sub.3 cycPr CH═CHCH.sub.2 -2-furanyl                            1076  7-OCH.sub.3 cycPr n-butyl                                                1077  7-OCH.sub.3 cycPr C.tbd.C-Et                                             1078  7-OCH.sub.3 cycPr C.tbd.C-iPr                                            1079  7-OCH.sub.3 cycPr C.tbd.C-cycPr                                          1080  7-OCH.sub.3 cycPr C.tbd.C-2-pyridyl                                      1081  7-OCH.sub.3 cycPr C.tbd.C-3-pyridyl                                      1082  7-OCH.sub.3 cycPr C.tbd.C-2-turanyl                                      1083  7-OCH.sub.3 cycPr C.tbd.C-3-furanyl                                      1084  7-OCH.sub.3 cycPr C.tbd.C-2-thienyl                                      1085  7-OCH.sub.3 cycPr C.tbd.C-3-thienyl                                      1086  7-OCH.sub.3 cycPr CH═CH-Et                                           1087  7-OCH.sub.3 cycPr CH═CH-iPr                                          1088  7-OCH.sub.3 cycPr CH═CH-cycPr                                        1089  7-OCH.sub.3 cycPr CH═CH-2-pyridyl                                    1090  7-OCH.sub.3 cycPr CH═CH-3-pyridyl                                    1091  7-OCH.sub.3 cycPr CH═CH-2-furanyl                                    1092  7-OCH.sub.3 cycPr CH═CH-3-turanyl                                    1093  7-OCH.sub.3 cycPr CH═CH-2-thienyl                                    1094  7-OCH.sub.3 cycPr CH═CH-3-thienyl                                    1095  7-OCH.sub.3 cycPr CH.sub.2 --C.tbd.C-cycPr                               1096  7-OCH.sub.3 cycPr CH.sub.2 --C.tbd.C-2-furanyl                           1097  7-OCH.sub.3 cycPr CH.sub.2 CH═CH-cycPr                               1098  7-OCH.sub.3 cycPr CH.sub.2 CH═CH-2-furanyl                           1099  7-OCH.sub.3 cycPr CH═CHCH.sub.2 -cycPr                               1100  7-OCH.sub.3 cycPr CH═CHCH.sub.2 -2-furanyl                           1101  7-pyrazol-6-yl cycPr n-butyl                                             1102  7-pyrazol-6-yl cycPr C.tbd.C-Et                                          1103  7-pyrazol-6-yl cycPr C.tbd.C-iPr                                         1104  7-pyrazol-6-yl cycPr C.tbd.C-cycPr                                       1105  7-pyrazol-6-yl cycPr C.tbd.C-2-pyridyl                                   1106  7-pyrazol-6-yl cycPr C.tbd.C-3-pyridyl                                   1107  7-pyrazol-6-yl cycPr C.tbd.C-2-furanyl                                   1108  7-pyrazol-6-yl cycPr C.tbd.C-3-furanyl                                   1109  7-pyrazol-6-yl cycPr C.tbd.C-2-thienyl                                   1110  7-pyrazol-6-yl cycPr C.tbd.C-3-thienyl                                   1111  7-pyrazol-6-yl cycPr CH═CH-Et                                        1112  7-pyrazol-6-yl cycPr CH═CH-iPr                                       1113  7-pyrazol-6-yl cycPr CH═CH-cycPr                                     1114  7-pyrazol-6-yl cycPr CH═CH-2-pyridyl                                 1115  7-pyrazol-6-yl cycPr CH═CH-3-pyridyl                                 1116  7-pyrazol-6-yl cycPr CH═CH-2-furanyl                                 1117  7-pyrazol-6-yl cycPr CH═CH-3-furanyl                                 1118  7-pyrazol-6-yl cycPr CH═CH-2-thienyl                                 1119  7-pyrazol-6-yl cycPr CH═CH-3-thienyl                                 1120  7-pyrazol-6-yl cycPr CH.sub.2 --C.tbd.C-cycPr                            1121  7-pyrazol-6-yl cycPr CH.sub.2 --C.tbd.C-2-furanyl                        1122  7-pyrazol-6-yl cycPr CH.sub.2 CH═CH-cycPr                            1123  7-pyrazol-6-yl cycPr CH.sub.2 CH═CH-2-furanyl                        1124  7-pyrazol-6-yl cycPr CH═CHCH.sub.2 -cycPr                            1125  7-pyrazol-6-yl cycPr CH═CHCH.sub.2 -2-furanyl                        1126  6,7-OCH.sub.2 O-- cycPr n-butyl                                          1127  6,7-OCH.sub.2 O-- cycPr C.tbd.C-Et                                       1128  6,7-OCH.sub.2 O-- cycPr C.tbd.C-iPr                                      1129  6,7-OCH.sub.2 O-- cycPr C.tbd.C-cycPr                                    1130  6,7-OCH.sub.2 O-- cycPr C.tbd.C-2-pyridyl                                1131  6,7-OCH.sub.2 O-- cycPr C.tbd.C-3-pyridyl                                1132  6,7-OCH.sub.2 O-- cycPr C.tbd.C-2-furanyl                                1133  6,7-OCH.sub.2 O-- cycPr C.tbd.C-3-furanyl                                1134  6,7-OCH.sub.2 O-- cycPr C.tbd.C-2-thienyl                                1135  6,7-OCH.sub.2 O-- cycPr C.tbd.C-3-thienyl                                1136  6,7-OCH.sub.2 O-- cycPr CH═CH-Et                                     1137  6,7-OCH.sub.2 O-- cycPr CH═CH-iPr                                    1138  6,7-OCH.sub.2 O-- cycPr CH═CH-cycPr                                  1139  6,7-OCH.sub.2 O-- cycPr CH═CH-2-pyridyl                              1140  6,7-OCH.sub.2 O-- cycPr CH═CH-3-pyridyl                              1141  6,7-OCH.sub.2 O-- cycPr CH═CH-2-furanyl                              1142  6,7-OCH.sub.2 O-- cycPr CH═CH-3-furanyl                              1143  6,7-OCH.sub.2 O-- cycPr CH═CH-2-thienyl                              1144  6,7-OCH.sub.2 O-- cycPr CH═CH-3-thienyl                              1145  6,7-OCH.sub.2 O-- cycPr CH.sub.2 --C.tbd.C-cycPr                         1146  6,7-OCH.sub.2 O-- cycPr CH.sub.2 --C.tbd.C-2-furanyl                     1147  6,7-OCH.sub.2 O-- cycPr CH.sub.2 CH═CH-cycPr                         1148  6,7-OCH.sub.2 O-- cycPr CH.sub.2 CH═CH-2-furanyl                     1149  6,7-OCH.sub.2 O-- cycPr CH═CHCH.sub.2 -cycPr                         1150  6,7-OCH.sub.2 O-- cycPr CH═CHCH.sub.2 -2-furanyl                     1151  7-CONH.sub.2 cycPr n-butyl                                               1152  7-CONH.sub.2 cycPr C.tbd.C-Et                                            1153  7-CCNH.sub.2 cycPr C.tbd.C-iPr                                           1154  7-CONH.sub.2 cycPr C.tbd.C-cycPr                                         1155  7-CONH.sub.2 cycPr C.tbd.C-2-pyridyl                                     1156  7-CONH.sub.2 cycPr C.tbd.C-3-pyridyl                                     1157  7-CONH.sub.2 cycPr C.tbd.C-2-furanyl                                     1158  7-CONH.sub.2 cycPr C.tbd.C-3-furanyl                                     1159  7-CONH.sub.2 cycPr C.tbd.C-2-thienyl                                     1160  7-CONH.sub.2 cycPr C.tbd.C-3-thienyl                                     1161  7-CONH.sub.2 cycPr CH═CH-Et                                          1162  7-CONH.sub.2 cycPr CH═CH-iPr                                         1163  7-CONH.sub.2 cycPr CH═CH-cycPr                                       1164  7-CONH.sub.2 cycPr CH═CH-2-pyridyl                                   1165  7-CONH.sub.2 cycPr CH═CH-3-pyridyl                                   1166  7-CONH.sub.2 cycPr CH═CH-2-furanyl                                   1167  7-CONH.sub.2 cycPr CH═CH-3-furanyl                                   1168  7-CONH.sub.2 cycPr CH═CH-2-thienyl                                   1169  7-CONH.sub.2 cycPr CH═CH-3-thienyl                                   1170  7-CONH.sub.2 cycPr CH.sub.2 --C.tbd.C-cycPr                              1171  7-CONH.sub.2 cycPr CH.sub.2 --C.tbd.C-2-furanyl                          1172  7-CONH.sub.2 cycPr CH.sub.2 CH═CH-cycPr                              1173  7-CONH.sub.2 cycPr CH.sub.2 CH═CH-2-furanyl                          1174  7-CONH.sub.2 cycPr CH═CHCH.sub.2 -cycPr                              1175  7-CONH.sub.2 cycPr CH═CHCH.sub.2 -2-furanyl                        ______________________________________                                          *Unless otherwise noted, stereochemistry is (+/-) and in R.sup.2, all          double bonds are trans.                                                  

                  TABLE 3                                                          ______________________________________                                           #STR52##                                                                        -                                                                             #STR53##                                                                        -                                                                             #STR54##                                                                        -                                                                             #STR55##                                                                        -                                                                             #STR56##                                                                       Ex. #   W      X      Y    Z    R.sup.1                                                                             R.sup.2                                 ______________________________________                                         2001  CH     CCl      CH   N    CF.sub.3                                                                            C.tbd.C-nPr                                 2002 CH CCl CH N CF.sub.3 C.tbd.C-Bu                                           2003 CH CCl CH N CF.sub.3 C.tbd.C-iBu                                          2004 CH CCl CH N CF.sub.3 C.tbd.C-tBu                                          2005 CH CCl CH N CF.sub.3 C.tbd.C-Et                                           2006 CH CCl CH N CF.sub.3 C.tbd.C-Me                                           2007 CH CCl CH N CF.sub.3 C.tbd.C-Ph                                           2008 CH CCl CH N CF.sub.3 C.tbd.C-2-Pyridyl                                    2009 CH CCl CH N CF.sub.3 C.tbd.C-3-Pyridyl                                    2010 CH CCl CH N CF.sub.3 C.tbd.C-4-Pyridyl                                    2011 CH CCl CH N CF.sub.3 C.tbd.C-2-furanyl                                    2012 CH CCl CH N CF.sub.3 C.tbd.C-3-furanyl                                    2013 CH CCl CH N CF.sub.3 C.tbd.C-2-thienyl                                    2014 CH CCl CH N CF.sub.3 C.tbd.C-3-thienyl                                    2015 CH CCl CH N CF.sub.3 CH═CH-cycPr                                      2016 CH CCl CH N CF.sub.3 CH═CH-iPr                                        2017 CH CCl CH N CF.sub.3 CH═CH-nPr                                        2018 CH CCl CH N CF.sub.3 CH═CH-Bu                                         2019 CH CCl CH N CF.sub.3 CH═CH-iBu                                        2020 CH CCl CH N CF.sub.3 CH═CH-tBu                                        2021 CH CCl CH N CF.sub.3 CH═CH-Et                                         2022 CH CCl CH N CF.sub.3 CH═CH-Me                                         2023 CH CCl CH N CF.sub.3 CH═CH-Ph                                         2024 CH CCl CH N CF.sub.3 CH═CH-2-Pyridyl                                  2025 CH CCl CH N CF.sub.3 CH═CH-3-Pyridyl                                  2026 CH CCl CH N CF.sub.3 CH═CH-4-Pyridyl                                  2027 CH CCl CH N CF.sub.3 CH═CH-2-furanyl                                  2028 CH CCl CH N CF.sub.3 CH═CH-3-furanyl                                  2029 CH CCl CH N CF.sub.3 CH═CH-2-thienyl                                  2030 CH CCl CH N CF.sub.3 CH═CH-3-thienyl                                  2031 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2032 CH CCl CH N CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2033 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2034 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2035 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2036 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2037 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2038 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2039 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2040 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2041 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2042 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2043 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2044 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-cycPr                               2045 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-iPr                                 2046 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-nPr                                 2047 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Bu                                  2048 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-iBu                                 2049 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-tBu                                 2050 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Et                                  2051 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Me                                  2052 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Ph                                  2053 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-2-Pyridyl                           2054 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-3-Pyridyl                           2055 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-4-Pyridyl                           2056 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-2-furanyl                           2057 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-3-furanyl                           2058 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-2-thienyl                           2059 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-3-thienyl                           2060 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-cycPr                             2061 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-iPr                               2062 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-nPr                               2063 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Bu                                2064 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-iBu                               2065 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-tBu                               2066 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Et                                2067 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Me                                2068 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Ph                                2069 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-2-Pyridyl                         2070 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-3-Pyridyl                         2071 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-4-Pyridyl                         2072 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-2-furanyl                         2073 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-3-furanyl                         2074 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-2-thienyl                         2075 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-3-thienyl                         2076 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                            CH.sub.3                                    2077 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2        2078 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2079 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 CH.sub.3                  2080 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                    2081 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -tBu                      2082 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -Ph                       2083 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                                    2084 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -3-Pyridyl                                                    2085 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -4-Pyridyl                                                    2086 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -2-furanyl                                                    2087 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -3-furanyl                                                    2088 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -2-thienyl                                                    2089 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -3-thienyl                                                    2090 CH CH CH N CF.sub.3 C.tbd.C-cyc                                          Pr                                          2091 CH CH CH N CF.sub.3 C.tbd.C-iPr                                           2092 CH CH CH N CF.sub.3 C.tbd.C-nPr                                           2093 CH CH CH N CF.sub.3 C.tbd.C-Et                                            2094 CH CH CH N CF.sub.3 C.tbd.C-3-Pyridyl                                     2095 CH CH CH N CF.sub.3 C.tbd.C-2-furanyl                                     2096 CH CH CH N CF.sub.3 C.tbd.C-3-furanyl                                     2097 CH CH CH N CF.sub.3 C.tbd.C-2-thienyl                                     2098 CH CH CH N CF.sub.3 C.tbd.C-3-thienyl                                     2099 CH CCl N CH CF.sub.3 C.tbd.C-iPr                                          2100 CH CCl N CH CF.sub.3 C.tbd.C-nPr                                          2101 CH CCl N CH CF.sub.3 C.tbd.C-Bu                                           2102 CH CCl N CH CF.sub.3 C.tbd.C-iBu                                          2103 CH CCl N CH CF.sub.3 C.tbd.C-tBu                                          2104 CH CCl N CH CF.sub.3 C.tbd.C-Et                                           2105 CH CCl N CH CF.sub.3 C.tbd.C-Me                                           2106 CH CCl N CH CF.sub.3 C.tbd.C-Ph                                           2107 CH CCl N CH CF.sub.3 C.tbd.C-2-Pyridyl                                    2108 CH CCl N CH CF.sub.3 C.tbd.C-3-Pyridyl                                    2109 CH CCl N CH CF.sub.3 C.tbd.C-4-Pyridyl                                    2110 CH CCl N CH CF.sub.3 C.tbd.C-2-furanyl                                    2111 CH CCl N CH CF.sub.3 C.tbd.C-3-furanyl                                    2112 CH CCl N CH CF.sub.3 C.tbd.C-2-thienyl                                    2113 CH CCl N CH CF.sub.3 C.tbd.C-3-thienyl                                    2114 CH CCl N CH CF.sub.3 CH═CH-cycPr                                      2115 CH CCl N CH CF.sub.3 CH═CH-iPr                                        2116 CH CCl N CH CF.sub.3 CH═CH-nPr                                        2117 CH CCl N CH CF.sub.3 CH═CH-Bu                                         2118 CH CCl N CH CF.sub.3 CH═CH-iBu                                        2119 CH CCl N CH CF.sub.3 CH═CH-tBu                                        2120 CH CCl N CH CF.sub.3 CH═CH-Et                                         2121 CH CCl N CH CF.sub.3 CH═CH-Me                                         2122 CH CCl N CH CF.sub.3 CH═CH-Ph                                         2123 CH CCl N CH CF.sub.3 CH═CH-2-Pyridyl                                  2124 CH CCl N CH CF.sub.3 CH═CH-3-Pyridyl                                  2125 CH CCl N CH CF.sub.3 CH═CH-4-Pyridyl                                  2126 CH CCl N CH CF.sub.3 CH═CH-2-furanyl                                  2127 CH CCl N CH CF.sub.3 CH═CH-3-furanyl                                  2128 CH CCl N CH CF.sub.3 CH═CH-2-thienyl                                  2129 CH CCl N CH CF.sub.3 CH═CH-3-thienyl                                  2130 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2131 CH CCl N CH CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2132 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2133 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2134 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2135 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2136 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                2137 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2138 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2139 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2140 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2141 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2142 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2143 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2144 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-iPr                                 2145 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-nPr                                 2146 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Bu                                  2147 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-iBu                                 2148 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-tBu                                 2149 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Et                                  2150 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Me                                  2151 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Ph                                  2152 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-2-Pyridyl                           2153 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-3-Pyridyl                           2154 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-4-Pyridyl                           2155 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-2-furanyl                           2156 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-3-furanyl                           2157 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-2-thienyl                           2158 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-3-thienyl                           2159 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-cycPr                             2160 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-iPr                               2161 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-nPr                               2162 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Bu                                2163 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-iBu                               2164 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-tBu                               2165 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Et                                2166 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Me                                2167 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Ph                                2168 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-2-Pyridyl                         2169 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-3-Pyridyl                         2170 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-4-Pyridyl                         2171 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-2-furanyl                         2172 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-3-furanyl                         2173 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-2-thienyl                         2174 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-3-thienyl                         2175 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                            CH.sub.3                                    2176 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2        2177 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2178 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 CH.sub.3                  2179 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                    2180 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                      2181 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                       2182 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                                    2183 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-Pyridyl                                                    2184 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -4-Pyridyl                                                    2185 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-furanyl                                                    2186 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-furanyl                                                    2187 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-thienyl                                                    2188 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-thienyl                                                    2189 CH CH N CH CF.sub.3 C.tbd.C-cyc                                          Pr                                          2190 CH CH N CH CF.sub.3 C.tbd.C-iPr                                           2191 CH CH N CH CF.sub.3 C.tbd.C-nPr                                           2192 CH CH N CH CF.sub.3 C.tbd.C-Et                                            2193 CH CH N CH CF.sub.3 C.tbd.C-3-Pyridyl                                     2194 CH CH N CH CF.sub.3 C.tbd.C-2-furanyl                                     2195 CH CH N CH CF.sub.3 C.tbd.C-3-furanyl                                     2196 CH CH N CH CF.sub.3 C.tbd.C-2-thienyl                                     2197 CH CH N CH CF.sub.3 C.tbd.C-3-thienyl                                     2198 CCl N CH CH CF.sub.3 C.tbd.C-cycPr                                        2199 CCl N CH CH CF.sub.3 C.tbd.C-iPr                                          2200 CCl N CH CH CF.sub.3 C.tbd.C-nPr                                          2201 CCl N CH CH CF.sub.3 C.tbd.C-Bu                                           2202 CCl N CH CH CF.sub.3 C.tbd.C-iBu                                          2203 CCl N CH CH CF.sub.3 C.tbd.C-tBu                                          2204 CCl N CH CH CF.sub.3 C.tbd.C-Et                                           2205 CCl N CH CH CF.sub.3 C.tbd.C-Me                                           2206 CCl N CH CH CF.sub.3 C.tbd.C-Ph                                           2207 CCl N CH CH CF.sub.3 C.tbd.C-2-Pyridyl                                    2208 CCl N CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                    2209 CCl N CH CH CF.sub.3 C.tbd.C-4-Pyridyl                                    2210 CCl N CH CH CF.sub.3 C.tbd.C-2-furanyl                                    2211 CCl N CH CH CF.sub.3 C.tbd.C-3-furanyl                                    2212 CCl N CH CH CF.sub.3 C.tbd.C-2-thienyl                                    2213 CCl N CH CH CF.sub.3 C.tbd.C-3-thienyl                                    2214 CCl N CH CH CF.sub.3 CH═CH-cycPr                                      2215 CCl N CH CH CF.sub.3 CH═CH-iPr                                        2216 CCl N CH CH CF.sub.3 CH═CH-nPr                                        2217 CCl N CH CH CF.sub.3 CH═CH-Bu                                         2218 CCl N CH CH CF.sub.3 CH═CH-iBu                                        2219 CCl N CH CH CF.sub.3 CH═CH-tBu                                        2220 CCl N CH CH CF.sub.3 CH═CH-Et                                         2221 CCl N CH CH CF.sub.3 CH═CH-Me                                         2222 CCl N CH CH CF.sub.3 CH═CH-Ph                                         2223 CCl N CH CH CF.sub.3 CH═CH-2-Pyridyl                                  2224 CCl N CH CH CF.sub.3 CH═CH-3-Pyridyl                                  2225 CCl N CH CH CF.sub.3 CH═CH-4-Pyridyl                                  2226 CCl N CH CH CF.sub.3 CH═CH-2-furanyl                                  2227 CCl N CH CH CF.sub.3 CH═CH-3-furanyl                                  2228 CCl N CH CH CF.sub.3 CH═CH-2-thienyl                                  2229 CCl N CH CH CF.sub.3 CH═CH-3-thienyl                                  2230 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2231 CCl N CH CH CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2232 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2233 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2234 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2235 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2236 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                2237 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2238 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2239 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2240 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2241 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2242 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2243 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2244 CH N CH CH CF.sub.3 C.tbd.C-iPr                                           2245 CH N CH CH CF.sub.3 C.tbd.C-nPr                                           2246 CH N CH CH CF.sub.3 C.tbd.C-Et                                            2247 CH N CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                     2248 CH N CH CH CF.sub.3 C.tbd.C-2-furanyl                                     2249 CH N CH CH CF.sub.3 C.tbd.C-3-furanyl                                     2250 CH N CH CH CF.sub.3 C.tbd.C-2-thienyl                                     2251 CH N CH CH CF.sub.3 C.tbd.C-3-thienyl                                     2252 N CCl CH CH CF.sub.3 C.tbd.C-cycPr                                        2253 N CCl CH CH CF.sub.3 C.tbd.C-iPr                                          2254 N CCl CH CH CF.sub.3 C.tbd.C-nPr                                          2255 N CCl CH CH CF.sub.3 C.tbd.C-Bu                                           2256 N CCl CH CH CF.sub.3 C.tbd.C-iBu                                          2257 N CCl CH CH CF.sub.3 C.tbd.C-tBu                                          2258 N CCl CH CH CF.sub.3 C.tbd.C-Et                                           2259 N CCl CH CH CF.sub.3 C.tbd.C-Me                                           2260 N CCl CH CH CF.sub.3 C.tbd.C-Ph                                           2261 N CCl CH CH CF.sub.3 C.tbd.C-2-Pyridyl                                    2262 N CCl CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                    2263 N CCl CH CH CF.sub.3 C.tbd.C-4-Pyridyl                                    2264 N CCl CH CH CF.sub.3 C.tbd.C-2-furanyl                                    2265 N CCl CH CH CF.sub.3 C.tbd.C-3-furanyl                                    2266 N CCl CH CH CF.sub.3 C.tbd.C-2-thienyl                                    2267 N CCl CH CH CF.sub.3 C.tbd.C-3-thienyl                                    2268 N CCl CH CH CF.sub.3 CH═CH-cycPr                                      2269 N CCl CH CH CF.sub.3 CH═CH-iPr                                        2270 N CCl CH CH CF.sub.3 CH═CH-nPr                                        2271 N CCl CH CH CF.sub.3 CH═CH-Bu                                         2272 N CCl CH CH CF.sub.3 CH═CH-iBu                                        2273 N CCl CH CH CF.sub.3 CH═CH-tBu                                        2274 N CCl CH CH CF.sub.3 CH═CH-Et                                         2275 N CCl CH CH CF.sub.3 CH═CH-Me                                         2276 N CCl CH CH CF.sub.3 CH═CH-Ph                                         2277 N CCl CH CH CF.sub.3 CH═CH-2-Pyridyl                                  2278 N CCl CH CH CF.sub.3 CH═CH-3-Pyridyl                                  2279 N CCl CH CH CF.sub.3 CH═CH-4-Pyridyl                                  2280 N CCl CH CH CF.sub.3 CH═CH-2-furanyl                                  2281 N CCl CH CH CF.sub.3 CH═CH-3-furanyl                                  2282 N CCl CH CH CF.sub.3 CH═CH-2-thienyl                                  2283 N CCl CH CH CF.sub.3 CH═CH-3-thienyl                                  2284 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2285 N CCl CH CH CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2286 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2287 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2288 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2289 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2290 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                2291 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2292 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2293 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2294 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2295 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2296 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2297 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2298 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-cycPr                               2299 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-iPr                                 2300 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-nPr                                 2301 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Bu                                  2302 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-iBu                                 2303 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-tBu                                 2304 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Et                                  2305 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Me                                  2306 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Ph                                  2307 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-2-Pyridyl                           2308 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-3-Pyridyl                           2309 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-4-Pyridyl                           2310 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-2-furanyl                           2311 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-3-furanyl                           2312 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-2-thienyl                           2313 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-3-thienyl                           2314 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-cycPr                             2315 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-iPr                               2316 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-nPr                               2317 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Bu                                2318 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-iBu                               2319 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-tBu                               2320 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Et                                2321 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Me                                2322 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Ph                                2323 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-2-Pyridyl                         2324 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-3-Pyridyl                         2325 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-4-Pyridyl                         2326 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-2-furanyl                         2327 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-3-furanyl                         2328 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-2-thienyl                         2329 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-3-thienyl                         2330 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                            CH.sub.3                                    2331 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2        2332 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2333 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 CH.sub.3                  2334 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                    2335 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                      2336 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                       2337 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                                    2338 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-Pyridyl                                                    2339 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -4-Pyridyl                                                    2340 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-furanyl                                                    2341 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-furanyl                                                    2342 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-thienyl                                                    2343 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-thienyl                                                    2344 N CH CH CH CF.sub.3 C.tbd.C-cyc                                          Pr                                          2345 N CH CH CH CF.sub.3 C.tbd.C-iPr                                           2346 N CH CH CH CF.sub.3 C.tbd.C-nPr                                           2347 N CH CH CH CF.sub.3 C.tbd.C-Et                                            2348 N CH CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                     2349 N CH CH CH CF.sub.3 C.tbd.C-2-furanyl                                     2350 N CH CH CH CF.sub.3 C.tbd.C-3-furanyl                                     2351 N CH CH CH CF.sub.3 C.tbd.C-2-thienyl                                     2352 N CH CH CH CF.sub.3 C.tbd.C-3-thienyl                                   ______________________________________                                          *Unless otherwise noted, stereochemistry is (+/-) and in R.sup.2, all          double bonds are trans.                                                  

Utility

The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated disease,. The compounds of formula (I) possess HIV reverse transcridtase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such aesays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIV reverse trarscriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

DNA Plasmids and in vitro RNA Transcripts

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The Iplasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini systemi II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at -70° C. The concentration of RNA was determined from the A₂₆₀.

Probes

Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosysteits (Foster City, Calif. DNA synthesizer by addition of biotii to the 5' terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCATACTA 3') was complementary to nucleotndes 889-912 of HXB2 and the pol biotinylated capture probe (5'-biotin-CCCTATCATTTTTGGTCCAT- 3') was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphates conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5' CTGTCTTACTTTGATAAAACCTC 3') was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5' CCCAGTATTTGTCTACAGCCTTCT 3') was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC. (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

Streptavidin Coated Plates

Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Ma.).

Cells and Virus Stocks

MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf Eerum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at -70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶ /mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

HIV RNA Assay

Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanddinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microslate Based Compound Evaluation in HIV-1 Infected MT-2 Cells

Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluatior of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volune in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a stieptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

In order to standardize thE virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC.) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the ANA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should he less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC₉₀ was found to be less than 20μM.

For antiviral potency tests, all mandpulations in microtiter plates, following the initial addition of 2× concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

HIV-1 RT Assay Materials and Methods

This assay measures HIV-1 FT RNA dependent DNA polymerase activity by the incozporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:

Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.

Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAE) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

Materials and Reagents

The template primer Poly (rA) oligo (dT)12-18 and dTTP were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/mL and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 μl/aliquot, dTTP at 9 μl/aliquot) and frozer at -20 C.

The 3H dTTP (2.5 mCi/mL in 10 mM Tricine at pH 7.6; specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 μl in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50% glycerol) were purchased from DUPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37 C. The 3H dTTP was aliquoted at 23.2 μl/microfuge tube (58 μCi) and frozen at -20 C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT buffer (80 mM KCl, 50 mM Tris HCl, 12 mM MgC12, mM DTT, 50 μM EGTA, 5 mg/mL BSA, 0.01% Triton-X 100, pH 8.2) and aliquoted at 10 μl/microfuge tube (10 Units/10 μl). One aliquot (enough for 8 assays) wes diluted further to 10 Units/100 μl and aliquoted into 8 tubes (1.25 Units/12.5 μl). All aliquots were frozen at -70 C.

The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing film were purchased from Millipore. The filter plate containing 0.65 μm pore size diethyl amino ethyl cellulose (DEAE) paper disks was pretreated with 0.3 M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 μl /well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were pulchased from Skatron Instruments. Microscint 20 scirtillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Becknan.

HIV-1 RT Assay

The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was diluted with RT buffer (containing 5 mg/mL BSA) to a concentration of 0.05 Units/10 μl or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 Units or 0.14 nM and 1 mg/mL respectively. The inhibitor and substrate mixture were diluted with RT buffer containing no BSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at -20 C. after use. A Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two tines (10 fold/dilution) from 31.25 μM to 3125 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 μM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 μM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 μM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 μg/mL of Poly (rA) oligo (dT)12-18 and 12.5 μM of dTTP (58 μCi 3H dTTP). The final substrate concentrations were 2.5 μg/mL and 5 μM respectively.

Using the Beckman Instrumerts Biomek robot, 10 μl of HIV-1 RT was combined with 20 μl of inhibitor in a 96 well U bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 μl of the substrate mixture was added to each well to initiate the reaction (total volume was 50 μl). The reactions were incubated at 37 C. and terminated after 45 minutes.

For method 1,200 μl of an ice-cold solution of 13% trichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyro)hosphate. The filter disks were washed 3 times (2.0 mL/wash, with 1 N HCl and 10 mM sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 mL of Beckman Ready Flow III scintillant was added, and the vials were counted for radioactivity for 1 minute.

For method 2, the assay was terminated with the addition of 175 1 μl/well of 50 mM EDTA at pH 8.0. Then 180 μl of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was appliel to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAE filter disks. Each well was washed 3 times with 200 μl of 0.3 M ammonium formate and 10 mM sodium pyrophosphate at pH 8.0. 50 μl of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.

The IC₅₀ values are calculated with the equation:

    IC.sub.50 =[Inh]/(1/fractional activity-1)

where the fractional activity=RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the IC₅₀ values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The IC₅₀ values in this range (generally 2 values) were averaged. A compound was considered active if its IC₅₀ was found to be less than 12μM.

Protein Binding and Mutant Resistance

In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibitiion of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/mL HSA, 1 mg/mL AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

Dosage and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of composition, suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's PharmacEutical Sciences, supra, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can le prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 ng of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volune propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of Components (a) and (b)

Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the reverse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferable, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams or each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. Phese enteric coated microtablets, particles, granule, or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered on a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A acompound of formula (I): ##STR57## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:A is O or S; W is N or CR³ ; X is N or CR⁴ ; Y is N or CR⁵ ; Z is N or CR⁶ ;provided that if two of W, X, Y, mnd Z are N, then the remaining are other than N; R^(a) is selected from H, CF₃, CF₂ H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰ ; R^(b) is selected from H, CF₃, CF₂ H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and phenyl substituted with 0-2 R¹⁰ ;alternatively, R^(a) and R^(b) together form --(CH₂)n--; R¹ is selected from CF₃, CF₂ H, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R² is selected from --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CH₇ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and --CH═CHCHR⁷ R⁸ ;provided that when either of R^(a) or R^(b) is phenyl, then R¹ is other than C₁₋₄ alkyl and C₃₋₅ cycloalkyl and R² is other than --(CH₂)_(p) CHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7b), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substitutes with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰ ;alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H, F, Cl, Br, and I;alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ; R⁷, at each occurrence, is selected from H and C₁₋₃ alkyl; R^(7a), at each occurrence, is seleced from H and C₁₋₃ alkyl; R^(7b), at each occurrence, is C₁₋₃ alkyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R¹⁰ ; R⁹, at each occurrence, is selected from H², OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰, at each occurrence, is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; R¹¹, at each occurrence, is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ; n, at each occurrence, is selected from 1, 2, 3, 4, and 5; and, p, at each occurrence, is selected from 0, 1, and
 2. 2. A compound according to claim 1, wherein:R^(a) is H; R^(b) is selected from H, CF₃, CF₂ H, cyclopropyl, CH═CH₂, and C₁₋₄ alkyl; R¹ is selected from CF₃, CF₂ H, C₁₋₃ alkyl, and C₃₋₅ cycloalkyl; and, R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.
 3. A compound according to claim 2, wherein:A is O; R¹ is selected from CF₃, CF₂ H, C₂ H₅, isopropyl, and cyclopropyl; R³ is selected from H, F, Cl, Br, I, OCH₃, and CH₃ ; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7b), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H and F; R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ; R⁷ is selected from H and CH₃ ; R^(7a) is selected from H and CH₃ ; R^(7b) is CH₃ ; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ; R⁹ is selected from H², OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and, p is selected from 1 and
 2. 4. A compound according to claim 3, wherein:R^(b) is selected from H, CF₃, CF₂ H, cyclopropyl, CH═CH₂, CH₃, and CH₂ CH₃ ; R¹ is selected from CF₃, CF₂ H, and cyclopropyl; R² is selected from --C.tbd.C--R⁸ and trans-CH═CR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, and I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;alternatively, R³ and R⁴ together form --OCH₂ O--; and, R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.
 5. A compound according to claim 1, wherein the compound is selected from:5-(1-Butynyl)-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-5-(1-Butynyl)-7-chloro-1,5-dihydro-3-phenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(5S)-7-Chloro-1,5-dihydro-5-(isopropylethynyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluozomethyl)-4,1-benzoxazepin-2(3H)-one; 1,5-Dihydro-7-fluoro-5-isopropylethynyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 1,5-Dihydro-7-fluoro-5-(3-methylbutyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-1,5-dihydro-5-(2-furan-2-ylethenyl)-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-1,5-dihydro-5-(2-furan-2-yl)ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-1,5-dihydro-5-(2-furanyl)ethynyl-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 5-Butyl-7-chloro-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazepin-2-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-cycloproplethynyl-1,5-dihydro-3-isopropyl-5-(trifluoromethy-)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-phenylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-isopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-cyclopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-isopropylethynyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Methoxy-5-(3-methylbutyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3R,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; 7-Chloro-5-(3-pyridylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Chloro-5-(3-pyrid-3-ylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-7-Fluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; trans-6,7-Difluoro-5-(2-isopropylethenyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-propyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(3-furanylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-cyclopropylethynyl-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-6,7-Difluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(3S,5S)-7-Chloro-5-cyclopropylethynyl-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (3S)-7-Chloro-5-cyclopropylethynyl)-1,5-dihydro-5-(trifluoromethyl)-4,1-benzocazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; (+)-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Chloro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Difluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-cyclopropyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2 (3H)-one; rel-(3S,5S)-7-Fluoro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-7-Fluoro-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Methylenedioxy-5-(2-cyclopropylethynyl)-1,5-dihydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-6,7-Methylenedioxy-5-2-cyclopropylethynyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dilydro-3-methyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one; and, rel-(3S,5S)-trans-6,7-Methylenedioxy-5-(2-cyclopropylethenyl)-1,5-dihydro-3-ethyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one;or a pharmaceutically acceptable salt form thereof.
 6. A compound according to claim 1, wherein, the compound is of formula II: ##STR58## or a stereoisomer or pharmaceutically acceptable salt form thereof.
 7. A compound according to claim 6, wherein, the compound is of formula IIa: ##STR59## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein R¹ is CF₃.
 8. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 1. 9. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 5. 10. A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt form thereof. 